Abstract
BACKGROUND: Non-classical manifestations such as neuropsychiatric manifestations in primary hyperparathyroidism (PHPT) have long been documented as symptoms of PHPT and are commonly reported by these patients, despite this connection still being a matter of debate, and they (per se) do not represent an indication of parathyroidectomy. OBJECTIVE: We aimed to overview the most recent findings regarding the link between depression and/or anxiety (D/A) in subjects confirmed with PHPT, including the impact of the surgery in improving their outcome. METHODS: This was a comprehensive review of English-based original studies published between January 2020 and October 2024. RESULTS: The studies (n = 16) included a total of 10,325 patients and an additional 152,525 patients with hypercalcemia (out of whom 13,136 had a PHPT diagnosis and 45,081 were at risk of PHPT diagnosis). Out of these subjects with PHPT, 10,068 underwent parathyroidectomy. Female prevalence was between 62.5 and 92%. Most individuals were over 50, with the youngest studied population having a mean age of 52.7 ± 13.8 years, and the oldest had a median of 71. Depression was documented based on ICD-10 codes (n = 3) and patients' records (n = 2), Depression Anxiety Stress Scales (DASS) (n = 2), Beck Depression Inventory (BDI) (n = 3), BDI-II (n = 3), Symptom Check List 90-revised (SCL) (n = 1), Hamilton Depression Rating Scale (HAM-D) (n = 2), HADS (n = 2), Patient Health Questionnaire-9 (n = 1), and European Quality of Life 5 Dimensions 3-Level Version (EuroQOL-5D-3L) (n = 1). Patient records' (n = 1) and ICD-10 codes (n = 2) were also used for anxiety. Most studies used questionnaires to identify anxiety in PHPT: DASS (n = 2), SCL90R (n = 1), Generalized Anxiety Disorder-7 (n = 1), HADS (n = 2), EuroQOL-5D-3L (n = 1), and State-Trait Anxiety Inventory (n = 1). Depression prevalence varied from 20-36.6% to 65.7% (scale-based assessment) and to 10.5% upon ICD-10. A rate of newly onset depression was reported of 10.7% and of 0.2% with concern to the prevalent suicidal ideation (an incidental rate of 0.4% after a median follow-up of 4.2 years). Most studies identified a moderate depression (when assessing its severity), affecting approximately one third of the surgery candidates. The prevalence of anxiety in PHPT varied between 10.4% and 38.6% (n = 8). Discordant results were generated when applying distinct questionnaires for the same population, and this might come as a potential bias. Other confounding factors are generated by the sub-population referred for surgery that typically displays a more severe parathyroid condition or non-endocrine overlapping conditions (e.g., related to the social or familial status). CONCLUSION: The modern approach of the patient with PHPT should be complex and go beyond the traditional frame. D/A had a high prevalence in the mentioned studies, associated with increased medication use. Yet, the underlying pathogenic mechanisms remain incompletely elucidated. No correlations between D/A and serum calcium levels were confirmed, while PTH had a slight positive correlation with depression. Parathyroid surgery appears to be beneficial for D/A as it improves the scores, prevalence, and severity. Cinacalcet might reduce depression scores, although more evidence is needed. Women are prone to both PHPT and D/A. The optimal method of D/A screening in PHPT remains to be determined, and the current scales need validation and perhaps adjustment for this specific population sub-group, while PHPT management should be refined upon D/A identification.