Surprising health benefits of our riskiest meds: Lithium, quetiapine, and clozapine.
Now that we’ve raised alarms over lithium toxicity, MAOI interactions, and lamotrigine rash, we’re going to change course with a final commandment that reminds us what psychopharmacology is really all about.
CHRIS AIKEN: Welcome to the Carlat Psychiatry Podcast, keeping psychiatry honest since 2003. I’m Chris Aiken, the journal’s editor and the coauthor of the textbook Prescribing Psychotropics.
KELLIE NEWSOME: And I’m Kellie Newsome, a psychiatric NP and a dedicated reader of every issue.
We are ready to close the book on this series with the final 10th commandment, one that puts the first 9 in persepective. First, let’s recap:
I.Do not worsen mental illness with psychiatric medications, like don’t use antidepressants in mania, or psychostimulants in psychosis.
II.Avoid stopping meds abruptly, particularly benzodiazepines, serotonergics, and lithium.
III.Prevent lithium toxicity by checking interactions, age, and renal function.
IV.Stop lamotrigine if any rash develops in the first 3 months.
V.Do not combine benzodiazepines and opioids in patients at high risk for overdose death.
VI.Honor thy MAOI interactions, but get up to date on the new diet data.
VII.Controlled substances shall be controlled, by you.
VIII.Avoid unwise medication combinations, like benzos and stimulants, or stimulants and antipsychotics.
IX.Avoid valproate, Depakote, in pregnancy.
Today we end with #10
X. Do not avoid effective medications just because they carry risks.
CHRIS AIKEN: In this episode, we’ll uncover a paradox in psychiatry. Some of the medications we avoid because of their medical risks are also the very ones that help patients live longer. We’re talking about lithium, quetiapine, and clozapine. But first, a preview of the CME quiz for this episode.
1. Clozapine is FDA-approved for treatment resistant schizophrenia and which other condition?
A. Treatment-resistant bipolar mania
B. Treatment-resistant aggression
C. Suicidal behavior in schizophrenia and schizoaffective disorder
D. Psychosis in Parkinson’s Disease
KELLIE NEWSOME: Good practice is not about avoiding risks. It is about balancing them against the benefits of treatment. Those benefits are not limited to symptom reduction and quality of life. Untreated psychiatric illness worsens physical health, causing inflammation and disrupting the endocrine, GI, cardiac, and immune systems. The net toll is about a 10 year reduction in lifespan, according to several studies of chronic mental illnesses like schizophrenia and bipolar disorder.
CHRIS AIKEN: One of those studies puts the risks of treatment in perspective. It was a study of 6 and a half million people from Sweden, and they found that bipolar disorder lowered life expectancy by 10 years, and not because of suicide. The top causes of death here were medical:
- Heart disease
- Diabetes mellitus
- Chronic obstructive pulmonary disease (COPD)
- Pneumonia and influenza
Suicide and accidental injuries were lower on the list. But when we turn to the appendix of that study we find a ray of hope. They further analyzed the life expectancy by medication use, and most evidence-based medication prolonged the lifespan. This is a secondary finding, so the ranking of these meds by mortality risk is not so reliable, but it is revealing. The meds that increased life expectancy the most were lithium, lamotrigine, and quetiapine (Seroquel).
KELLIE NEWSOME: Quetiapine? That’s a shocker. That med has nearly a dozen black box warnings. And the added weight and metabolic problems it brings can’t be the reason it is making people live longer. And lithium is not exactly free of medical risks either.
CHRIS AIKEN: Lithium didn’t surprise me as much. Lithium slows down two of the biological processes involved in aging; the way that DNA strands tend to shorten as we age, crumbling at their telomeric ends like the way the edges of a paperback book get raged with time, and epigenetic aging effects, where DNA is altered by process like methylation and chromatin remodeling. There’s even some evidence that animals live longer if they take a little lithium. But I wouldn’t expect the average person to live longer if they took quetiapine.
KELLIE NEWSOME: So it’s more that these medications are treating the mental illness – the bipolar disorder itself. In a lot of ways the brain is the captain of the ship – directing the endocrine, circadian, digestive, cardiac, and even the immune system. A healthier brain means a healthier body.
CHRIS AIKEN: That’s probably what is going on here, and that may explain why lithium, lamotrigine, and quetiapine lowered mortality the most.
KELLIE NEWSOME: Why is that?
CHRIS AIKEN: These three meds have the strongest antidepressant effects in bipolar disorder, at least among the options available in 2013. Lamotrigine lowers the risk of depression by 50%. And lithium and quetiapine had the strongest preventative effects against depression in a meta-analysis by Terrence Ketter. Mania and depression are both bad for health – some studies find manic symptoms take an even bigger toll, for example, on cardiovascular health than depression does. But while mania wins on severity, depression beats it out for frequency. Depression makes up 30-60% of the lifespan in bipolar disorder, compared to 5-10% for hypomania and mania. So meds like these that take a big chip out of the depressive pole are taking a giant step for physical health, one that – in the big picture – cancels out the various black box warnings that would dissuade us from using them.
KELLIE NEWSOME: So don’t let the lamotrigine rash, the renal compromise on lithium, or quetiapine’s metabolic risks dissuade you from using these drugs. Patients feel better when they take them, and that doesn’t necessarily come at a cost to their physical health. These meds prolong life for the average patient with bipolar disorder.
CHRIS AIKEN: If prolonging life is the goal of medicine. When I first learned about this study I was excited to share the news with my patients. “Quetiapine has a lot of medical risks, but people actually live longer when they take it.” And I went on like that for a couple of weeks until a dysthymic patient looked at me straight on and said “Dr. Aiken, don’t get me wrong – I’m not suicidal or anything – but – I don’t want to live a long life.”
KELLIE NEWSOME: That study came out in 2013, and since then new antipsychotics have come out for bipolar depression that are better tolerated than quetiapine, like lurasidone and lumateperone. And maybe those prolong life more than quetiapine, but we don’t have the data to say, and there are arguments that point the other way. Quetiapine is the only antipsychotic with robust preventative effects in bipolar disorder, and it has unique benefits for sleep and anxiety that other antipsychotics do not. On the other hand, we can see a lot of reasons to avoid quetiapine. Patients often call back after starting it – falling from the hypotension, or unable to rise out of bed form the sedation. And if they do make it past the starting line, there’s long-term weight gain. We’re certainly not saying you should give quetiapine to every patient with bipolar disorder, but you shouldn’t be afraid to use it. Rewind to our October 2021 episodes on the Best and Worst Antipsychotics in Mania to learn more about this rough gem.
CHRIS AIKEN: Turning to schizophrenia, we see something even more remarkable with the underutilized antipsychotic clozapine. It’s hard to imagine a psych med more dangerous than this one, with its 1 in 100 chance of causing potentially fatal agranulocytosis. Not mention seizures, arrhythmias, metabolic syndrome, and a side effect that recently surpassed agranulocytosis for causing fatality on clozapine: paralytic ileus. But here’s the surprise. When people with schizophrenia take clozapine, they live an average of 10 years longer compared to other antipsychotics, according to around a dozen studies. That’s hard to explain. This medication has more medical risks than the other antipsychotics, and it is selectively given to those with more severe illness, including those who self harm – clozapine is FDA approved for reducing suicidal behavior in schizophrenia and schizoaffective disorder. Some have speculated that these patients live longer because they get their labs checked more often, but I doubt that a monthly cbc is going to add another week to my life, much less 10 years. The best explanation I can come up with is that schizophrenia is a mind-body illness, and clozapine brings about a fuller recovery than other antipsychotics, and thus a longer life.
KELLIE NEWSOME: The way we approach this shines a light on stigma. I mean, if someone had breast cancer they are given all the options – partial mastectomy, total mastectomy, chemo, radiation. We don’t wait for it to get metastatic before bringing out the full armamentarium. But in schizophrenia we wait for 2 failed trials before offering clozapine, and even then only 1 in 5 patients in the US who are eligible for it actually end up taking it. If we were oncologists, this would be an embarrassment.
CHRIS AIKEN: Schizophrenia and bipolar disorder are not the only conditions where treatment extends life. People with ADHD live about 4 years longer on average if the disorder is treated. Stimulants have clear cardiac risks, but when ADHD is treated, people have fewer accidents and take better care of their medical health.
KELLIE NEWSOME: Quetiapine, lithium, and clozapine carry medical risks that might dissuade their use, but our job is to balance those risks with the benefits. And in the right patient, the balance is clear: They extend life rather than shortening it. But what about the quality of that life? Are these patients thriving, enjoying life, or are they struggling with daily tolerability problems – fatigue, emotional blunting, cognitive problems, nausea and tremor?
CHRIS AIKEN: Kellie I know you have a cool new study on that, but I can give my two cents from experience. When I started practice I did not want to prescribe lithium or clozapine because I thought patients would hate them. They would be intolerable. I figured those medications were for patients with refractory disorders who went to the hospital several times a year. I was wrong. Even though most of my patients function well enough to hold jobs, many have gone from struggling to thriving on those meds. And the idea that these are not tolerable – that is one of the biggest myths in the industry.
Most of the pharmaceutical advertising budget is spent trying to convince us that their meds are safe – they are normal, everybody’s using them. I realized this when patients with mild disorders started asking for antipsychotics to manage stress. The same patients would refuse a med like EMSAM – which has a low advertising budget – because it’s too scary. But if we look back in history, lithium was once heavily advertised as a health supplement. The wealthy flocked to lithium spas, and president Grover Cleveland ordered lithium water shipped to the white house.
When it comes to the side effects that matter most to patients, lithium has an edge. The rate of fatigue on lithium is 1 in 28, compared to 1 in 4 for most antipsychotics. Weight gain is less on lithium, and patients can do something to reduce it. Tell them to drink water instead of caloric beverages because lithium is going to make them thirsty. And lithium has Non-adherence to mood stabilizers and antipsychotics among persons with bipolar disorder - A nationwide cohort study a more favorable cognitive profile than the antipsychotics.
KELLIE NEWSOME: People vote with their feet, and when it comes to that bottom line, patients actually prefer lithium and clozapine, according to a fresh off the press Finnish study from the Journal of Affective Disorders by Jonne Lintunen and colleagues. They looked at 3 years of pharmacy fill rates for 33,000 patients with bipolar disorder, including clozapine. Finland has the highest rate of clozapine prescriptions in the world, and clozapine is used off label even in the US for refractory mania. The bottom line: Lithium and clozapine had the lowest rates of non-adherence. Lithium even beat out lamotrigine. Overall, adherence was higher for lithium and the anticonvulsants than it was for the antipsychotics, but quetiapine had one of the highest adherence rates in the antipsychotic class? Whatever side effects these meds have, they were outweighed by the changes they made in these patient’s lives.
CHRIS AIKEN: Lithium, quetiapine, and clozapine are not the only meds that are avoided for the wrong reason. We’ll cover more – including bupropion, trazodone, and disulfiram – in a future episode.
And now for the study of the day
Mood stabilizers and risk of all-cause, natural, and suicide mortality in bipolar disorder: A nationwide cohort study, by Pao-Huan Chen and colleagues from Acta Psychiatica Scandinavia.
Earlier in this podcast we talked about a 2013 study of mortality in bipolar disorder, and this 2023 study from Tawain updates those figures. They followed 26,000 patients with bipolar disorder over 16 years. Here’s what they found. All mood stabilizers lowered the risk of mortality by about 50% - both from suicide and from medical problems. The reduction in mortality was greatest with lithium.
KELLIE NEWSOME: Get more research updates like these through Dr. Aiken’s LinkedIn or Twitter feeds @ChrisAikenMD. Subscribe to our online journal and get $30 off your first year’s subscription with the promo code PODCAST. The Carlat Report is one of the few CME publications that depends entirely on subscribers. Thank you for helping us stay free of commercial support.