Clinical severity and calcium metabolism in patients with bipolar disorder

What was the study about?

• It was investigated whether and what connection there is between an imbalance in calcium homeostasis and psychiatric disorders. “Our results suggest that calcium homeostasis may play a role in BD patients and that PTH levels are correlated with the clinical severity of the disorder.”
• The study included 199 subjects from Naples and Catanzaro, 98 men and 101 women aged 18-65.
• The study ran from June 2019 to March 2020.
• Of these, 101 participants had a diagnosis of Biopolar I disorder.
• 51% of the participants were treated with lithium.

Summary:

• Parathyroid hormone (PTH), vitamin D and serum calcium play a key role in various physiological and pathological conditions.
• Vitamin D and PTH receptors are widely expressed in the central nervous system and are involved in the modulation of inflammatory reactions.
• Only a few studies have investigated the relationship between an imbalance in calcium homeostasis and psychiatric disorders.
• This study aims to investigate an imbalance of calcium homeostasis in patients with bipolar disorder (BD) and its impact on clinical outcome.
• We recruited 199 patients with BD who were assessed for depressive, manic and anxiety symptoms, affective temperament, childhood trauma and global functioning using validated assessment instruments. Serum calcium, vitamin D and PTH levels were determined in all patients.
• serum levels of Vit D and calcium were within the normal range (mean Vit D level in our sample: 42.57 ± 65.31 ng/ml, normal ranges: 30-100 ng/ml, mean serum calcium level in our sample: 9.42 ± 10.76 mg/dl, normal ranges: 9-10.7 mg/dl), while PTH levels were higher than normal (mean PTH levels in our sample: 45.6 pmol/L, normal ranges: 7-10 pmol/L).
• PTH levels correlated with several clinical characteristics, including diagnosis of bipolar disorder type I (BD-I), presence of psychotic symptoms, lithium treatment, suicidality, total number of acute episodes and hospitalizations (p < 0.0001), and seasonality (p < 0.05).
• In the regression analyses, higher PTH levels were predicted by earlier age at onset, number of hospitalizations, aggressive behaviors (p < 0.05), higher Childhood Trauma Questionnaire (CTQ) total score (p < 0.001), and treatment with lithium (p = 0.01).
• Our results suggest that calcium homeostasis may play a role in BD patients and that PTH levels are correlated with the clinical severity of the disorder.

Introduction:

Calcium homeostasis is involved in several physiological processes, such as the balance of the musculoskeletal system, immune modulation, the antioxidant defense system and several inflammatory processes [1]. Calcium homeostasis is largely regulated by an integrated hormonal system that modulates calcium transport in the gut, kidney and bone through the involvement of parathyroid hormone (PTH) [2], vitamin D (Vit D), serum ionized calcium and calcium-sensing receptor (CaR) [3]. Vitamin D stimulates the brain cells to produce various growth factors such as nerve growth factor (NGF), glial cell line-derived neurotrophic factor (GDNF) and neurotrophin 3 (NT3), thereby stimulating the protection and growth of neuronal cells. The Vit D receptor (VDR), which is mainly expressed in the central nervous system (CNS), particularly in the amygdala, regulates behavioral and emotional responses [4] and is involved in the modulation of inflammatory reactions. Its ligand, Vit D, is a membrane antioxidant that increases the gene expression of various antioxidants [5,6]. Vit D also decreases the activity of cytokines through inhibitory effects on the activation and expression of inflammatory factors such as interleukin 1 and 6, tumor necrosis factor-α (TNFα), nuclear factor kappa B (NF-κB) and other related genes [7].

In addition, there is evidence that Vit D modulates the biosynthesis of neurotransmitters, such as serotonin by tryptophan hydroxylase 2 (TPH2), and neurotrophic factors and thus significantly influences mood and its changes [8,9].

In addition, PTH regulates the levels of circulating and intracellular calcium in the CNS and induces apoptosis due to calcium overload [10]. Elevated PTH levels are associated with reduced regional cerebral blood flow [11], while the PTH-related protein (PTHrP) inhibits calcium channel activity and thus contributes to the maintenance of normal neuronal function [12]. PTH also promotes the conversion of Vit D into its active form [13] and is involved in neuroprotective and anti-inflammatory regulation [14]. High PTH concentrations could be associated with neuronal damage. In fact, a higher concentration of calcium can be found in the CNS due to a PTH imbalance. Calcium overload can lead to a disruption of neuronal signal transmission or to atrophy in the hippocampus, which is associated with the occurrence of psychiatric symptoms [15].

Several studies suggest that low blood levels of Vit D are involved in dementia, Parkinson’s disease and psychiatric disorders, particularly affective disorders [16,17]. In fact, Vit D deficiency appears to be strongly correlated with the severity of depressive symptoms, and a recent meta-analysis reported the positive effects of vitamin D supplementation in patients with depression [18]. In bipolar disorder (BD), a significant correlation was found between vitamin D deficiency and the severity of the disorder. This could be due to various factors. Calcium metabolism is directly involved in serotonin biosynthesis and correlates with mood swings and impulsive behavior [19]; in addition, a decrease in neuronal plasticity in various brain regions involved in bipolar disorder has been found as a result of vitamin D deficiency [20]. Finally, the generalized and chronic inflammation associated with calcium imbalance supports activation of the hypothalamic-pituitary axis, leading to a change in mood [21]. Therefore, calcium, Vit D and PTH levels can be used as markers for chronic inflammation and consequently for chronic neuroinflammation [21]. In fact, patients with an acute manic episode have lower serum concentrations of Vit D compared to healthy controls and patients in remission [22]. More recently, it has been suggested that the acute phase of BD is associated with an increase in plasma Vit D synthesis and with low-grade inflammation compared to healthy controls and psychotic disorders [23].

Despite the fact that several studies have shown the relationship between calcium metabolism and mood disorders, most of these studies have mainly focused on the effect of Vit D on depressive symptoms, while only a few studies have investigated the effect of changes in overall calcium homeostasis (including PTH and calcium levels) on the course of patients with bipolar disorder. PTH can be considered a more accurate marker of chronic calcium homeostasis imbalance.

In this study, we investigated the imbalance of calcium homeostasis in a sample of patients with bipolar disorder (BD); specifically, we examined whether serum levels of PTH, Vit D, and calcium influence the clinical presentation of bipolar disorder, symptom severity, and clinical outcome.

2. Methods

2.1. Participants

It is an observational naturalistic study. The patients were recruited consecutively in the psychiatric departments of the University of Campania “Luigi Vanvitelli” in Naples and the Mater Domini University Hospital in Catanzaro from June 2019 to March 2020. Patients were included in the study if they met the following criteria: (1) age between 18 and 65 years, (2) diagnosis of bipolar disorder type I or type II according to the Diagnostic and Statistical Manual of Mental Disorders-fifth edition (DSM-5) [24] and (3) willingness to participate in the study. Patients were excluded in case of: (1) inability to give written informed consent to participate in the study, (2) moderate or severe cognitive impairment, (3) comorbidity with a neurological disorder or drug and/or alcohol abuse, (4) pregnancy or puerperium, and (5) current treatment with medications that may alter calcium metabolism. All patients gave their written consent to participate in the study after receiving a full description of the objectives and design of the study. The study was conducted in accordance with the latest version of the Declaration of Helsinki and was approved by the Ethics Committee of the University of Campania “Luigi Vanvitelli” (number: N001567/28.01.2018.).

2.2. Procedures and measures

2.2.1. Sociodemographic and clinical characteristics

Patients’ clinical and sociodemographic characteristics, including gender, age at study entry, employment status, education level, family history of psychiatric illness, mode of onset, number of lifetime affective episodes, pattern of illness progression, treatments, suicidal ideation, and previous psychiatric hospitalizations, were recorded using an ad hoc schedule.

The severity of depressive and anxious symptoms was assessed using the Hamilton Depression Rating Scale (HAM-D) [25] and the Hamilton Rating Scale for Anxiety (HAM-A) [26]manic symptoms with the Mania Rating Scale [27] and affective temperaments with the short Italian version of the Temperament Evaluation of Memphis, Pisa, Paris and San Diego ( TEMPS-M for short) [28] recorded. The presence of emotional, sexual or physical abuse in childhood and of emotional or physical neglect was investigated using the Childhood Trauma Questionnaire-Short Form (CTQ-SF) [29].

2.2.2. Evaluation of serum parameters

To determine the serum levels of calcium, 25-OH-vitamin D and PTH, biological samples were taken from all patients, which were examined during recruitment in the laboratories of the two participating sites according to a standardized procedure. Calcium was measured using standard laboratory methods. Blood was centrifuged and serum was stored at -30 ˚C for 25-OH-vitamin D and PTH and analyzed by chemiluminescence immunoassays using appropriate kits (Diasorin Liaison; ADVIA Centaur).

2.2.3. Statistical evaluations

Descriptive statistics were calculated for sociodemographic and clinical characteristics as well as for other relevant assessment tools. The data is presented as mean values and standard deviations (SD) or frequencies and percentages (%). The Kolmogorov-Smirnov test was used to check the normality of the distribution of our sample. Correlation analyses were performed to investigate the relationship of serum levels of PTH, Vit D and calcium with continuous variables. Student’s t-test for independent samples was performed to examine the association of serum levels of PTH, Vit D and calcium with discrete variables. Linear regression analyses were performed using PTH, Vit D and calcium as dependent variables, and the independent variables were selected among those that showed a positive association in the univariate analyses and among those identified as most relevant in the literature [30]. The level of statistical significance was set at p < 0.05. Statistical analyses were performed using the Statistical Package for Social Sciences, Version 21 (SPSS, Chicago, IL, USA).

3. Results

3.1. Socio-demographic characteristics of the sample

The total sample consisted of 199 patients, of whom 98 were male (49%) and 101 female (51%), with a mean age of 47.1 ± 13.2 years. Half of them were in a steady relationship (53%) and were employed (55%). Seventy percent of the sample had a positive history of psychiatric disorders, and 109 subjects (55%) had received a diagnosis of BD-I. The mean age at onset of the disease was 27.0 ± 9.5 years, the duration of the disease was 20 years (±12.4). Half of the sample (51%) was being treated with lithium. The blood values were 42.6 ± 21.6 pmol/L for PTH, 42.6 ± 65.3 ng/mL for Vit D and 9.4 ± 0.8 mg/mL for calcium. The most important sociodemographic and clinical characteristics of the sample are listed in Table 1.

3.2. Univariate analyses

The correlations between the serum parameters and the clinical variables are shown in Table 2 and Table 3. Serum PTH levels were inversely correlated with age at disease onset (p < 0.01), the years of education (p < 0.05) and the age at the first depressive episode (p < 0.01); on the contrary, they were directly correlated with the total number of hospitalizations (p < 0.01) and the depressive (p < 0.0001), manic (p < 0.001) and hypomanic episodes (p < 0,01). Higher PTH values were found in patients with a diagnosis of BD-I (p < 0.0001), regular course of illness (p = 0.028), aggressive behavior (p = 0.009), psychotic symptoms during depressive (p < 0.0001) or manic episodes (p < 0.0001), seasonal course of illness (p = 0.023), use of atypical antipsychotics (p = 0.013) and a history of suicide attempts (p < 0.0001) was found. In addition, PTH was positively correlated with depressive (p < 0.0001), anxious (p < 0.01), cyclothymic (p < 0.001) and irritable (p < 0.0001) temperaments in the short TEMPS-M. Emotional neglect, emotional abuse, physical abuse, physical neglect, trauma and the CTQ total score were also strongly correlated (p < 0.0001) with elevated PTH levels. No correlation was found with gender, educational and occupational level, psychiatric history, medication use, predominant polarity (both depressive and manic) during the illness, treatment with anticonvulsants, typical antipsychotics or selective serotonin reuptake inhibitor (SSRI) antidepressants.

The serum levels of calcium were positively correlated with the years of education and with the HAM-A total score (p < 0.05). Serum levels of Vit D were positively associated with age at first psychiatric contact and were inversely correlated with total number of depressive episodes (p < 0.05) and cyclothymic temperament (p < 0.05). In addition, higher Vit D levels were reported in patients without psychotic symptoms during the acute phases of the disorder (p < 0.05).

3.3. Multivariate analyses

The results of the linear regression analysis are shown in Table 4. The model was run to assess the independent predictors associated with PTH levels. Patients with higher PTH levels were more likely to have a younger age at onset (p = 0.032), a higher number of hospitalizations (p = 0.017), aggressive behavior (0.092), a higher score on the CTQ scale (p = 0.001), and to be on treatment with lithium (p = 0.013).

4. Discussion

The main finding of our study is the association of high PTH levels with disease severity (i.e., highly recurrent patients with positive history of childhood trauma and impulsivity), which may be due to several factors. First, PTH levels can affect the level of chronic neuroinflammation, which is significantly associated with higher disease burden and more severe clinical presentation of the disorder [31], leading to altered neurotransmission [32] and dysfunctional brain development through reduced induction of nerve growth factor [33,34], reduced immune regulation and anti-inflammatory actions [35,36]. Secondly, the association between high PTH levels and age at onset could be due to chronic Vit D deficiency triggering the neuroinflammatory process and eventually leading to full-blown disease [37,38]. This finding confirms previous evidence that calcium imbalance is associated with earlier age at disease onset and poorer long-term outcome in terms of symptom severity, social functioning and number of relapses and hospitalizations [39]. In our study, both age at onset and number of hospitalizations predicted higher PTH levels, confirming the role of PTH in worsening the long-term course of BD. Third, the association between aggressive behavior and high PTH levels may be explained by the role of calcium imbalance in the synthesis of serotonin neurotransmitters via the tryptophan pathways [40]. In fact, the involvement of serotonin in the regulation of impulsivity and its clinical correlates leads to reduced serotonin levels in the brain, causing antisocial/aggressive behavior, feelings of anger and self-harm [41,42,43,44]. In BD, the change in serotonin synthesis is associated with aggressive behavior [40,45] and a higher risk of suicide attempts [46]. However, we did not measure serotonin levels in our sample, so this explanation deserves further study to confirm it. Fourth, the CTQ total score is also associated with higher PTH levels. Childhood trauma increases the lifetime risk of developing BD [47] and is associated with higher clinical severity [48] and a more severe clinical course (i.e. rapid cycling, early age of onset, suicide attempts and more depressive episodes) [49]. In BD patients, a history of trauma in childhood leads to difficulties in affective regulation, impulse control, cognitive function and neurobiological changes due to the epigenetic consequences of early trauma. The hypothalamic-pituitary-adrenal (HPA) axis, serotonergic transmission, inflammation, neuroplasticity and calcium signaling are involved in these modifications [50]. It is possible that the levels of PTH, Vit D and calcium are influenced by traumatic events, as is the case with the HPA axis; nevertheless, the explanation deserves further investigation. Finally, according to our regression model, higher PTH levels are predicted by pharmacological treatment with lithium. This finding is consistent with available studies that have found that long-term treatment with lithium stimulates parathyroid function, leading to secondary hyperparathyroidism [51]. Although the actual prevalence of this phenomenon is unclear, around 25% of patients treated with lithium exhibit disturbances in calcium homeostasis [52]. Lithium interacts with the calcium-sensing receptor and causes intracellular changes in calcium levels in the parathyroid principal cells, thereby influencing PTH secretion [53].

According to the univariate analyses, several severity and outcome indices, including diagnosis of bipolar I disorder, presence of psychotic features in acute phases, seasonality, and history of suicide attempts, are associated with elevated PTH levels. All of these indices are correlated with poorer outcome and higher psychological distress in BD [54,55,56,57]. An obvious but less significant relationship was found between calcium and Vit D levels and symptom severity. This finding, which is consistent with previous studies [58], confirms the role of calcium metabolism in mood stability, with patients with an imbalance in calcium metabolism having a poorer outcome and higher disease severity.

Unlike reported in other studies, in our sample, clinical outcome variables correlated more frequently with serum levels of PTH than with those of Vit D. This may be due to the fact that in our sample, serum levels of Vit D and calcium were within the normal range (mean Vit D levels in our sample: 42.57 ± 65.31 ng/mL, normal ranges: 30-100 ng/mL, mean serum calcium level in our sample: 9.42 ± 0.76 mg/dl, normal ranges: 9-10.7 mg/dl), while PTH levels were higher than normal (mean PTH levels in our sample: 45.6 pmol/L, normal ranges: 7-10 pmol/L). This finding, which points to secondary hyperparathyroidism, confirms the presence of a chronic imbalance in calcium metabolism in BD patients. In addition, unlike PTH, Vit D and calcium levels are also influenced by other external variables (e.g. diet, ultraviolet UV light, physical activity) and therefore represent a less accurate expression of chronic imbalance of calcium metabolism [59].

To our knowledge, this is one of the few studies available that has investigated the relationship between elevated PTH levels and clinical severity and outcome in patients with BD. Its main strengths include the simultaneous determination of PTH, Vit D and calcium levels, which allows analysis of the entire metabolic axis, and the relatively large sample size compared to other available studies. However, the study also has some important limitations, one of which is the lack of a control group. In addition, the cross-sectional design of the study limits conclusions about causality. A longitudinal evaluation of serum parameters will allow us to clarify the variability of PTH, calcium and Vit D levels in relation to psychopathological variables. Another possible limitation is the lack of retrospective assessment of serum parameters, especially levels at the onset of the disease and during its acute phases. However, we have planned follow-up studies to compensate for this limitation.

In summary, elevated PTH levels correlate with poorer outcome and high psychological distress in BD patients. Our results suggest that calcium imbalance may influence the long-term outcome of bipolar disorder and emphasize the importance of routine determination of PTH, Vit D and calcium levels in these patients as markers of clinical severity.

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