‘Prescribing Cascades’ Common in Psychiatry—and Require Monitoring, Management, Education
Researchers found a number of psychiatric medications that may trigger adverse events serious enough to require prescription of more medication. Experts don’t agree on how to handle them.
Getty Images/iStock/Oleg Elkov
About one-fourth of problematic “prescribing cascades” identified in a recent analysis of pharmacy records involved medications commonly used to treat psychiatric disorders, such as lithium, antipsychotics, antiepileptics, and antidepressants, according to findings issued in the Journal of the American Geriatrics Society.
A prescribing cascade occurs when a medication triggers an adverse event or side effect that requires treatment with additional medication. Usually, physicians are aware that it is drug-induced, but sometimes the patient’s reaction is misinterpreted as a new condition, wrote lead author Atiya K. Mohammad, M.Sc., at University Medical Centre Groningen in the Netherlands, and colleagues.
Prescribing cascades can lead to an excess medication burden, which is of particular concern in older adults, Mohammad and colleagues noted. However, “despite being assessed as problematic in general, some prescribing cascades are unavoidable in individual cases that relate to a condition or situation for which there is no alternative treatment,” they added.
Psychopharmacology experts interviewed by Psychiatric News said it is important for prescribers to frequently check for adverse events and to educate patients about them. In some cases, managing a side event with additional medication may be preferable to discontinuing successful pharmacotherapy and risking decompensation.
“I think prescribing cascades do happen, but not commonly,” said Stephen M. Stahl, M.D., Ph.D., Distinguished Health Sciences Clinical Professor of Psychiatry and Neurosciences at the University of California, San Diego, and director of psychopharmacology for the California Department of State Hospitals. “They seem to be presented as overly problematic, which may set off unnecessary alarms. Most can be managed without the need for additional medication, with dose reduction, dose splitting, and/or substituting medications as needed.”
Mohammad and colleagues identified 79 prescribing cascades from a literature review, which were then reviewed by an expert multidisciplinary panel that classified 66 of them as potentially problematic. The researchers examined Dutch community pharmacy data for adults from 2015 to 2020 to calculate an adjusted sequence ratio (aSR) for these cascades, which reflects how often physicians prescribe the first (index) medication, followed by the second medication (marker) within a set time period, relative to the overall prescribing patterns of these medications in a population. An aSR greater than 1 indicates a likely prescribing cascade, with higher aSRs indicating greater probability.
Managing Lithium’s Side Effects
Of the 41 clinically significant prescribing cascades identified by the researchers, 10 involved commonly prescribed psychiatric drugs. The psychotropic prescribing cascade with the highest sequence ratio in the study involved lithium-induced tremors, for which patients were prescribed propranolol (aSR 2.91). Also high on the list were lithium-induced parkinsonism, treated with tertiary amines/dopaminergics (aSR 2.18), and lithium-induced hypothyroidism, which led to thyroid hormone treatment (aSR 2.17).
One of the limitations of the study is that it did not examine the reason patients were taking an index medication—or their response to it, said Balwinder Singh, M.D., M.S., a bipolar disorder specialist, assistant professor of psychiatry, and associate program director at the Mood Fellowship at Mayo Clinic, who reviewed the study. “It’s important to look at the whole picture.
“It’s important to look at the whole picture,” said Balwinder Singh, M.D., M.S. “If someone is taking lithium for bipolar disorder and is doing really well on it, then we try to manage” the tremors or hypothyroidism.
Courtesy of Balwinder Singh
“If someone is taking lithium for bipolar disorder and is doing really well, then we try to manage the side effects,” Singh said. “The risk of decompensation for patients when lithium is discontinued is much greater than their risk from being treated for hypothyroidism, for example. Levothyroxine can take care of it.”
Singh said the evidence shows that lithium is a highly effective first-line treatment that reduces mood episodes for many patients and is extremely underutilized, particularly in the United States. It has also been proven to reduce risk of mild cognitive impairment, hospitalization, and suicidality, long-term, for individuals with bipolar disorder. In one recent study, Singh and colleagues found that among patients who discontinued lithium due to developing chronic kidney disease, 61% experienced a subsequent mood episode, compared with just 10% of those who remained on the medication, according to the report in the Journal of Clinical Psychopharmacology in 2023.
When it comes to thyroid dysfunction, about one-third of 154 adults with bipolar disorder enrolled at the Mayo Clinic Bipolar Biobank who were taking long-term lithium therapy eventually developed thyroid disorder, according to a study by Singh and colleagues published in Brain Sciences in 2023. Among those who did, hypothyroidism (low thyroid) was most common. Women were twice as likely to experience lithium-induced thyroid dysfunction and had a shorter average treatment duration prior to developing it (17 years versus 43 years for men).
Yet only two of the patients on lithium who developed thyroid dysfunction discontinued the medication, while the rest were successfully managed with medication, according to the study. As for tremors, Singh said they often subside after an initial adjustment period, but if the dose is stable and optimized, and tremors continue, beta blockers can be considered—after cardiac dysfunction is ruled out with an EKG.
Singh was puzzled, however, that the study found a strong association between lithium and parkinsonism. “That is a rare side effect with lithium treatment, and is more likely to be seen with antipsychotics,” he said.
Other Prescribing Cascades
Other clinically significant prescribing cascades included antipsychotic-triggered parkinsonism, which required tertiary amines/dopaminergics, (aSR 2.08), and antipsychotic-induced hyperprolactinemia/oligomenorrhea, which required prolactin inhibitors (aSR 2.12).
Swapnil Gupta, M.D., associate professor and medical director of ambulatory psychiatry at Mount Sinai Morningside Hospital, said that antipsychotics trigger numerous other prescribing cascades not examined in the study, including metabolic disorder (metformin), hyperlipidemia (statins), obesity (semaglutide), tardive dyskinesia (deutetrabenazine or valbenazine), tremors (anticholinergic), and constipation (laxatives).
“Prescribing cascades are definitely an issue in psychiatry,” Gupta said. “The way to avoid them is to optimize the dosage rather than reach for another medication as the solution.... The best way to reduce the impact of the side effect is to drop the dose of the offending agent.”
Gupta also frequently reevaluates patients’ medications with an eye toward what can be tapered or discontinued. For example, an anticholinergic prescribed to manage a patient’s tremors after initiating an antipsychotic in most cases can be discontinued after six months when tremors typically subside.
The remaining prescribing cascades involving psychiatric medications identified is this study were:
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Antiepileptics caused urinary tract infections, which required systemic antibiotics (aSR 1.37).
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Antidepressants caused migraines, which required analgesics or antipyretics (aSR 1.33).
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Antidepressants caused parkinsonism, which required tertiary amines/dopaminergics (aSR 1.16).
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Antiepileptics caused oedema peripheral, which required high-ceiling diuretics (aSR 1.15).
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Antidepressants caused urinary incontinence, which required medications for urinary frequency and incontinence (aSR 1.07). ■
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Published in print: December 1, 2024 – December 31, 2024
Published online: 2 December 2024
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