The FDA keeps recalling medications for contamination with NDMA, and the contamination was recently found in the first-line antidote for antipsychotic weight gain: metformin.
Published On: 11/2/2020
Duration: 13 minutes, 13 seconds
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: It started in 2018 with a blood pressure medication, valsartan. Scientists at an online pharmacy were screening products for potential carcinogens when they saw an alarming peak in a probably carcinogent, N-Nitrosodimethylamine (NDMA) levels. Valsartan was recalled in July of 2018, and it was followed by the recalls of 5 other NDMA-contaminated medications:
- November 2018: The angiotensin II receptor blockers irbesartan and losartan.
- September 2019 and January 2020: The over the counter reflux medicines ranitidine and nizatidine
- That recalls started hitting closer to home between May and October 2020 when the FDA recalled 179 batches of Metformin ER.
So what is N-Nitrosodimethylamine (NDMA)?
Dr. Aiken: First, what it’s not. NDMA is not NMDA. NMDA the glutamatergic receptor involved in the mechanisms of psychiatric medications that antagonize the NMDA receptor – ketamine and lamotrigine; experimental antidepressants like amantadine, riluzole, memantine, and dextromethorphan; and drugs of abuse like phencyclidine (PCP), alcohol, and two that have both therapeutic properties and abuse potential: MDMA and ketamine. These drugs reduce the effects of excess glutamate. A little bit of glutamate is good, but too much is toxic.
Kellie Newsome: NDMA is also toxic, but in a different way. It’s a carcinogen that causes mutations in DNA, and it is directly damaging to the liver. Even small amounts are deadly, and there have been several prominent homicides where NDMA was used as a poison, resulting in death through hepatotoxicity. On the other hand, NDMA is everywhere. It’s a by-product of waste water treatment with chlorine. That water flows through our taps and into the soil where the NDMA collects in the plants and vegetables we eat. NDMA is also one of cancer-causing nitrosamines that forms in smoked and grilled meats. It’s particularly high in smoked sausages. Nitrosamines are found in beers, cheeses, sausages, bacon, and foods that are smoked or pickled in salt. So how much NDMA are these recalled medications producing? With ranitidine, NDMA levels rose 9-fold higher than the upper safety level for medications. But that safety level which the FDA set for medications seems very conservative – 0.096 mcg/day. The typical diet has about twice as much NDMA – and if you’re drinking a lot of alcohol or eating smoked meats your typical diet will have a lot more NDMA in it. Part of the reason this safety limit is set so low is that the FDA assumes that the NDMA from medications is on-top of the NDMA already present in our daily foods. A pound of steak has 3 times a much NDMA as the upper safety limit for medications.But what really matters is cancer. There the FDA has given us some data on the first recalled medication: valsartan. If 8,000 people took valsartan at the max dose dose for 4 years while the drug was contaminated, there would be one additional case of cancer.
Dr. Aiken: We still don’t know the cause of all this NDMA contamination. The best guess is that it's a byproduct of the manufacturing process. But the problem points to a troubling trend in drug quality. As manufacturing has shifted overseas in the past two decades, we're seeing more problems with medications. 40% of U.S. medications are manufactured overseas, and even when they are produced in the U.S. around 80% of the ingredients come from abroad.
It's difficult for the FDA to regulate overseas manufacturing because they can't make surprise visits. They have to work through governmental agencies to arrange their inspections, allowing the drug companies precious time to prepare for the inspectors. Most of the problems have come from manufacturers in India and China (Katherine Eban details them in Bottle of Lies. The original valsartan contamination came from a Chinese firm, Zhejiang Huahai. This firm changed their manufacturing process in 2011 and, against regulation, did not announce the change to the FDA (here's the FDA's letter detailing the failings).
Kellie Newsome: Back to Metformin. Our Nov-Dec issue has an article that tells you how to figure out whether your patient’s metformin has been contaminated by NDMA and what to do about it. The situation was alarming to us, as the number of contaminated metformin batches kept growing, and we worried that it was only a matter of time before they all were tested and all found to be contaminated. But there is some reassurance there – the FDA did test some batches that are clean and we have guidance on how to find those batches in the article.
Kellie Newsome: So, Metformin is used for diabetes and polycystic ovarian disease, but why do we use it in psychiatry?
Dr. Aiken: In psychiatry we use it to prevent weight gain on antipsychotics. It's the best studied antidote for that side effect. The American Psychiatric Association recommends it in their 2020 treatment guidelines for antipsychotics in schizophrenia, and a dozen randomized controlled trials have found that it reduces antipsychotic associated weight gain by about 7 pounds on average.
And this benefit is not just cosmetic. Metformin lowers the risk of diabetes in people taking antipsychotics by reducing insulin resistance. It reduces cholesterol and triglyceride levels on antipsychotics, and it prevents prolactin elevations on antipsychotics, and high prolactin can lead to problems like sexual dysfunction, breast milk secretion, cancer risk, and osteopenia.
Here’s a tip on using metformin. Don’t wait until the antipsychotic weight gain gets out of hand before starting it. Metformin works best when started early, particularly with high-weight gaining meds like olanzapine and clozapine where it can be started soon after the antipsychotic.
Metformin may also have direct benefits on the brain. When used for traditional medical purposes, like diabetes and polycystic ovarian disease, metformin reduces depression, and a randomized controlled trial found that it treats depression when added to an antidepressant even when patients don’t have diabetes.
Kellie Newsome: So how should patients substitute if their medication is recalled or they don’t want to risk it with the metformin instant release?
Dr. Aiken: For the NDMA-contaminated reflux medications ranitidine and nizatidine, there are alternatives that have been tested and are free of NDMA: famotidine (Pepcid), cimetidine (Tagamet), esomeprazole (Nexium), lansoprazole (Prevacid), and omeprazole (Prilosec).
There is no clear subsitutute for metformin, but liraglutide, which is used for diabetes and weight loss, has a promising study for antipsychotic weight gain. Liraglutide also has direct brain benefits – protecting brain cells (neuroprotective) and increasing sensitivity to insulin in the brain (which helps memory and cognition – a promising possibility borne out by one uncontrolled study in depressed patients with memory problems).
Kellie Newsome: And now for the word of the day….Alexithymia
Alexithymia is a personal trait characterized by the inability to identify and describe emotions experienced by one's self or others. Alexithymia is not a diagnosis but a trait found in many disorders, most notably antisocial personality disorder, substance abuse, and autism. Last week we defined a similar term, dyssymbole, which refers to difficult that people with schizophrenia have in describing their inner experiences.
The difference between alexithymia and dyssymbole is really one of degree – dyssymbole is more of a psychotic level detachment from the self – it is part of what makes it hard to understand the experience of a person with schizophrenia. In alexithymia the person appears to be having normal human emotions like anxiety, but they seem unable to talk about their feelings or even to simply name them – but they can otherwise talk about personal events in their lives and they still appear to act on those feelings in ways that most anyone would – although they act in more extreme ways like substance abuse and violence perhaps because they are unable to metabolize the feelings.
Kellie Newsome: Do you try to add psychotherapy to your medication visits? Then we have a holiday treat for you. This winter we’re featuring interviews on how to weave therapy into the medication visit, starting next with a conversation with Michael Posternak. If you like this podcast, share it with a friend, and rate us in your podcast store. It’s easy, you just press one of them stars.
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