The study included 105 acromegaly patients (Table 1). The mean IGF-1-level at diagnosis was 2.3 (1.8) times upper limit of normal (xULN). At follow-up, 91% of the patients with acromegaly were biochemically controlled [3].

In the group of acromegaly patients, no significant differences were observed between patients with or without psychiatric diagnoses as regards to age at pituitary diagnosis, sex, pituitary adenoma size, treatment (both surgical, medical and radiation), number of comorbidities, IGF-l-level at diagnosis and at follow-up or pituitary insufficiency (data not shown). The same accounted for all comorbidity, except for hypertension that was more prevalent in the group of acromegaly with a psychiatric diagnosis (p < 0.05) (data not shown).

Acromegaly patients were diagnosed at a younger age (48.8 ± 14.9 years) compared to NFPA patients (57.2 ± 16.6 years, p < 0.001), with similar sex distribution (Table 1). Pituitary adenomas were smaller in patients with acromegaly (17.9 ± 9.9 mm) than in patients with NFPAs (22.9 ± 10.6 mm, p < 0.001). More acromegaly patients were operated compared to NFPA patients (85.7 vs. 60.2%, p < 0.001). Among operated patients, the number of surgeries did not differ between the two groups (p = 0.075). More acromegaly patients received replacement therapy for hypopituitarism compared to NFPA patients (25.7 vs. 16.1%, p = 0.042). Among patients treated for hypopituitarism, the number of replaced hormone axes did not differ between groups (p = 0.59). The risk of psychiatric diagnoses was significantly higher in acromegaly patients (27.6%) compared to NFPA patients (14.7%, p = 0.006).

In pituitary patients with a psychiatric diagnosis, a larger proportion of acromegaly patients were operated compared to NFPA patients (p = 0.02), while the number of surgeries in operated patients was comparable (p = 0.33) (Table 2). The groups were comparable regarding age at pituitary diagnosis, sex, pituitary adenoma size and pituitary insufficiency.

The age at psychiatric diagnosis did not differ between groups (p = 0.41). However, patients with acromegaly were diagnosed 6.0 [0.9, 16.5] years after their pituitary diagnosis, while patients with NFPAs were diagnosed 0.2 [− 3.5, 3.4] years prior to their pituitary diagnosis (p = 0.002).

Depression predominated in both groups, but the risk was significantly higher in acromegaly patients compared to patients with NFPAs (23.8 vs. 12.3%, p = 0.009). Anxiety disorder was the second-most frequent diagnosis (4.8% in acromegaly patients vs. 3.3% in NFPA patients, p = 0.53). Bipolar disorder was less frequent but similar in both acromegaly and NFPA patients (1.0 vs. 0.5%, p = 0.55). In acromegaly patients, psychoses (1.0%) and eating disorders (1.9%) were observed, the latter comprising one patient with an unspecified eating disorder, and one with overeating associated with other psychological disturbances. In relation to the acromegaly diagnosis, the patients were diagnosed approximately 7 years before and 4 years after, respectively. Diagnoses of ADHD (n = 2) and PTSD (n = 1) were only present in NFPA group.

All patients with psychiatric diagnoses received psychotropic medications, except for one NFPA-patient and two acromegaly patients. A larger proportion of acromegaly patients were treated with antidepressant drugs compared to NFPA patients (24.8 vs. 13.7%, p = 0.02). The use of antipsychotic (4.8 vs. 1.4%, p = 0.12) or anxiolytic drugs (5.7 vs. 1.9%, p = 0.07) did not differ significantly between groups. Other psychotropic medications were used by 1.9% of acromegaly patients and 2.4% of NFPA patients, including mood-stabilizers (lithium, lamotrigine and valproate) and methylphenidate.

Significantly more acromegaly patients were admitted to a psychiatric ward compared to NFPA patients (5.7 vs. 0.5%, p = 0.006). Among acromegaly patients with psychiatric diagnoses, a daily use of opioids was noted in 27.6% with a median morphine equivalent dose of 25 [20–45] mg. Opioid use was associated with an increased risk of arthropathy in the acromegaly cohort (p = 0.009) (data not shown).

Using a binary regression model, acromegaly patients had a significantly higher risk of depression compared to NFPA patients, with an unadjusted RR of 1.93 (95% CI [1.18, 3.17], p = 0.009). When adjusting for factors including age at pituitary disease, pituitary adenoma size, pituitary surgery and hypopituitarism, the increased risk retained statistical significance (RR 1.86, 95% CI [1.02, 3.39], p = 0.04). In a subgroup analysis excluding NFPA patients without pituitary surgery, acromegaly patients had an increased risk of depression compared to NFPA patients (RR 1.89, 95% CI [1.07, 3.35], p = 0.03).

The risk of anxiety disorder in acromegaly compared to NFPA was 1.44 (95% CI [0.47, 4.41], p = 0.53) for the unadjusted model. In subgroup analysis excluding all NFPA patients without pituitary surgery, the relative risk was 1.01 (95% CI [0.32, 3.21, p = 0.99).

A total of 1283 publications were identified, of which 227 duplicates were removed. Of the remaining publications, 964 were excluded based on title or abstract. Following a detailed evaluation of the remaining 92 publications, 8 studies with a total of 1387 patients were deemed eligible for inclusion based on presentation of data regarding the prevalence of psychopathology or psychiatric diagnoses among acromegaly patients, compared to a control group of either healthy subjects or NFPA patients (Fig. 1, Table 3).

Based on the available data, the meta-analysis was divided into two categories: The risk of depression (Fig. 2) or anxiety (Fig. 3). These categories were further divided by comparison cohorts: “acromegaly vs. NFPA” and “acromegaly vs. healthy”.

Forest plot of the risk of depression in acromegaly patients compared to NFPA patients and healthy controls. Abbreviations: RR: Risk Ratio, CI: Confidence Interval

Forest plot of the risk of anxiety in acromegaly patients compared to NFPA patients and healthy controls. Abbreviations: RR: Risk Ratio, CI: Confidence Interval

The meta-analysis revealed a higher pooled risk of depression in acromegaly patients (RR 2.11, 95% CI [1.67, 2.66]), with low heterogeneity (I2 = 0.0%). When comparing acromegaly patients to NFPA patients, the risk remained increased (RR 1.82, 95% CI [1.33, 2.50]). Also, the risk was increased 2.51 times compared to healthy controls (95% CI [1.78, 3.53]).

Likewise, the meta-analysis showed an increased pooled risk of anxiety in acromegaly patients (RR 1.54, 95% CI [1.01, 2.36]), with low-moderate heterogeneity (I2 = 29.55%). When comparing to NFPA patients, the risk of anxiety in acromegaly patients was 86% higher (RR 1.86, 95% CI [1.07, 3.21]). Compared to healthy controls, the RR was increased at 1.40, but did not reach statistical significance (95% CI [0.76, 2.59]).