More hospitals and clinics are now offering ketamine therapy to patients for severe depression, post-traumatic stress disorder and other mental health problems that have not responded to other treatments.
While ketamine is a safe drug when used under medical supervision, it has one little-known complication: it can be very harmful to a developing fetus. It should not be used during pregnancy.
But a new study suggests that ketamine prescribers are not paying enough attention to this risk and should do more to ensure that patients receiving ketamine are not pregnant and are aware of the need to use contraception while undergoing treatment that lasts several months.
The new article in the Journal of Clinical Psychiatry It was written by researchers at the University of Michigan’s academic medical center, Michigan Medicine. It reports the results of a survey and document review conducted at ketamine clinics across the country, and a review of records from the ketamine clinic for depression at UM Health.
Overall, they found wide variation in policies, practices and warnings about ketamine use in relation to pregnancy and reproduction, even though the 119 clinics that responded to the survey report treating a total of more than 7,000 patients with ketamine per month and estimate that one-third of the patients they see are female and premenopausal.
Main findings
More than 75% of responding clinics said they have a formal pregnancy screening process, but only 20% actually require a pregnancy test at least once before or during treatment.
More than 90% of clinics reported mentioning pregnancy as a contraindication to ketamine treatment in their informed consent documents and/or discussions. But less than half of clinics reported discussing specific potential risks with patients.
The researchers also analyzed informed consent documents on the websites of 70 other ketamine clinics. In total, 39 percent did not include information about pregnancy in their documents, and those that did were generally vague.
In terms of contraceptive counseling, only 26% of clinics responding to the survey said they discuss the potential need for contraception with patients taking ketamine. Less than 15% of clinics specifically recommend or require the use of contraception during treatment.
This is especially surprising, the authors say, because more than 80% of clinics reported prescribing long-term maintenance ketamine, with nearly 70% saying their patients receive care for more than six months and many saying patients receive ketamine for a year or more.
A review of the records of 24 patients treated with ketamine at the UM clinic in the past showed that all had taken a pregnancy test before starting treatment and weekly during treatment, but only half had documentation in their records that they were using contraception.
Inspiration for study
Lead author Dr. Rachel Pacilio, a psychiatrist who recently joined Michigan Medicine as a clinical assistant professor after completing her residency at UM Health, said the idea for the study came to her during a rotation in the perinatal psychiatry clinic.
Patients who were pregnant or had recently given birth asked him about ketamine as an option for their treatment-resistant depression. They had heard about the drug’s potential positive impact when administered intravenously as an off-label use of a common anesthetic, or as an intranasal esketamine spray that is marketed as Spravato and approved by the U.S. Food and Drug Administration.
“There were few guidelines available to physicians other than the general recommendation to avoid ketamine in pregnant patients, due to its unknown potential impact on the fetus or a breastfed newborn,” Pacilio says. “That sparked our interest in conducting a survey of clinics to see how they were managing this issue during their intake processes, initial courses of treatment, and during the maintenance therapy phase. To our knowledge, this is the first time this topic has been investigated.”
Variation in supervision
Clinics offering intravenous ketamine require specialized staff and post-administration monitoring for each session. Additionally, the FDA specifically requires at least two hours of in-person observation after administration of intranasal Spravato to ensure safety and monitor for complications.
In contrast, other ketamine formulations can be administered outside of a clinical setting with minimal supervision. Some clinics surveyed reported prescribing sublingual ketamine for home use.
The new study did not include ketamine providers that offer online, direct-to-consumer treatment exclusively through telehealth consultations. It is unclear how these companies address concerns about reproduction and other safety aspects despite their growing popularity among patients.
“These data suggest that a large number of patients could be pregnant or become pregnant while receiving ketamine treatment via multiple routes of administration. This risk increases with the duration of therapy, which can last weeks for initial treatment and a year or more for maintenance treatment,” Pacilio said. “Many patients are unaware they are pregnant in the first few weeks, and animal studies of ketamine are very concerning about potential harm to the fetus during this period.”
She noted that while many psychotropic medications have been widely studied and found to be safe for use during pregnancy, including a variety of antidepressants, antipsychotics, and other psychiatric drugs, there is no data to support the use of ketamine for psychiatric illness during pregnancy.
Pacilio noted that the FDA’s risk mitigation program for Spravato, the nasal form of ketamine, does not include any pregnancy provisions. A warning issued by the FDA last fall about the risks of compounded forms of ketamine available online also does not mention any pregnancy precautions.
“The variability in practice we observed across community clinics in this study is stark,” Pacilio said. “The field really needs to standardize reproductive counseling, pregnancy testing, and contraceptive recommendation during ketamine treatment.”
If a woman becomes pregnant while receiving ketamine treatment and must stop taking the drug for the remainder of her pregnancy, she is at risk for a relapse of depression that could continue after the baby is born. Perinatal and postpartum depression are major risk factors for a variety of problems in both the mother and the baby.
Need for standard orientation
After sharing her findings about the UM patients in the new study with leaders of the UM Health ketamine clinic, Pacilio said the clinic began recommending the use of highly reliable forms of contraception for patients who might become pregnant while receiving ketamine treatment.
Small, independent community clinics offering ketamine therapy may not have the same resources as a large clinic like UM’s, so standard counseling may be of particular benefit to them.
Interventions are needed that include improved patient education, with an emphasis on the need to prevent pregnancy during ketamine treatment during the informed consent process, routine pregnancy testing before and during treatment for appropriate patients, and effective contraceptive counseling. Many of these measures could be easily implemented and have the potential to have a positive impact on public health.
“Ketamine is a really effective treatment that can save lives in the right patients, but not everyone is a suitable candidate for it,” he said. “As psychiatrists, we need to make sure that this treatment is delivered in a way that benefits patients and prevents harm.”
In a commentary published in the journal about the U-M team’s findings, psychiatrist and journal editor Marlene Freeman, MD, wrote that based on the new findings, “it is imperative that best practices for women of reproductive age be determined and utilized with regard to the use of ketamine and esketamine.” She added that this is especially important in light of the changing landscape of abortion-related laws.
Freeman also noted that those who have used ketamine in any form during pregnancy, as well as other psychotropic medications, can join the National Pregnancy Registry for Psychiatric Medications during pregnancy and help provide much-needed information about the impacts of these medications.
In addition to Pacilio, the study authors include Jamarie Geller, MD, MA, a psychiatry fellow at U-M, and faculty members Juan F. Lopez, MD; Sagar V. Parikh, MD; and Paresh D. Patel, MD, Ph.D.
The study was funded by the UM Department of Psychiatry.