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Incidence of new-onset depression was no lower for adults with primary hyperparathyroidism (PHPT) treated with early parathyroidectomy compared with nonoperative management, observational Veterans Affairs data showed.

In a trial emulation of 40,231 veterans with PHPT and no history of depression, the 5-year weighted cumulative incidence of depression was 11% in those who underwent early parathyroidectomy and 9% for nonsurgical patients, reported Lia Delaney, MD, MS, of Stanford University School of Medicine in California, and colleagues.

By year 10, the weighted cumulative incidence of depression was 18% in both groups, they detailed in .

The adjusted rate for new-onset depression didn't significantly differ between the two management types (HR 1.05, 95% CI 0.94-1.17).

"[W]e were not able to find a benefit of early parathyroidectomy on the development of new depression when compared with nonoperative management," Delaney's group said.

But the "findings are relevant to preoperative discussions regarding the benefits and risks of operative management and can help guide patient decision-making in the preoperative period, especially in populations who may be at higher risk of adverse outcomes with surgery," they wrote.

Parathyroidectomy is currently the only definitive treatment for PHPT, they noted. Several have suggested a link with a subsequent improvement in depression and other neurocognitive symptoms.

But author Michael Yeh, MD, of UCLA David Geffen School of Medicine in Los Angeles, pointed out "major inherent design flaws" in many of these prior studies.

"In patients who may have been primed to expect improvements in neuropsychiatric health, surgery could have a powerful placebo effect, leading one to conclude that sham surgery might be the only legitimate (though obviously unethical) control arm," Yeh argued.

The current study stands out perhaps more because of its methods than its findings, he pointed out.

Target trial emulation involves asking a causal question in the form of a hypothetical randomized trial, then emulating components of the trial using observational data.

Delaney and co-authors used cloning to address immortal time bias, "an important source of confounding in observational studies that involve an intervention (in this case, parathyroid surgery) that may occur in a delayed fashion after an exposure (in this case, the biochemical diagnosis of primary hyperparathyroidism)," Yeh wrote. "Cloning involves using statistical magic to create a 'clone' for each patient included in the study to mitigate imbalances between treatment arms."

While outcomes in the study were limited to depression diagnoses, Yeh said it's possible parathyroidectomy could hold more nuanced neuropsychiatric benefits.

It "may be that the neurocognitive effects of parathyroidectomy are more subtle than a clinical diagnosis of depression and would be better evaluated outside of claims data, with broader evaluations of quality of life and function," Delaney and co-authors pointed out.

The researchers also suggested that while the overall rate of incident depression wasn't affected by parathyroidectomy, the binary definition of depression used in the study might not have been sensitive enough to capture subtle changes, they noted.

The analysis included Veterans Health Administration patients newly diagnosed with PHPT from 2000 through 2019. Most of the cohort was managed nonoperatively (91.8%), and 8.2% were managed with parathyroidectomy within 1 year of diagnosis.

A biochemical diagnosis of PHPT was defined as an elevated serum calcium level (over 10.2 mg/dL) and an elevated parathyroid hormone level (over 65 ng/mL) in the subsequent 6 months. Those with secondary or tertiary hyperparathyroidism were excluded based on an estimated glomerular filtration rate below 30 mL/min/1.73 m² at any time in the year prior to PHPT diagnosis.

A new diagnosis of depression was based on ICD-9 and ICD-10 codes. Patients had to have one inpatient diagnosis code for depression or two outpatient diagnosis codes for depression within 2 years of each other.

Those who underwent early parathyroidectomy had a higher average parathyroid hormone level, were more likely to have a serum calcium level of 1 mg/dL or more above the upper limit of normal, were younger, mostly white, and more likely to have a lower Charlson Comorbidity Index score.

Early parathyroidectomy patients had similar rates of post-traumatic stress disorder, anxiety, alcohol use disorder, opioid use disorder, and history of stroke, but lower rates of diabetes, hypothyroidism, and coronary artery disease.

In a subgroup analysis, risk of new onset depression also didn't favor either management strategy when patients were divided by age (younger than 65 vs 65 and older) or baseline calcium level (under 11.3 mg/dL vs 11.3 mg/dL or higher).

There were 2,938 patients who underwent delayed parathyroidectomy, occurring at a median of 2.6 years after diagnosis. There was also no difference in the estimated effect of parathyroidectomy when patients were censored at the time of delayed parathyroidectomy (HR 1.03, 95% CI 0.93-1.15).

Delaney's group listed the study's observational nature as one limitation. PHPT most commonly affects women, but the veteran patient population is about 90% men.

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