Jerker Hetta

Case-control study on symptoms and signs of "asymptomatic" primary hyperparathyroidism.

BACKGROUNDnSymptoms, signs, and treatment of mild primary hyperparathyroidism (HPT) are controversial.nnnMETHODSnOne hundred two patients with HPT and matched controls were recruited from 5202 females attending population-based mammography screening at age 55 to 75 years. Patients total serum calcium averaged 10.40 +/- 0.564 mg/dL and intact serum parathyroid hormone 58 +/- 33 ng/L. All patients lacked knowledge of their disease. Questions revealed traditional symptoms of HPT in 24% of cases and 43% of controls (P = .01). All individuals underwent the same biochemical analyses, bone mass determination, and questionnaires on symptoms, illnesses, medications, and background variables.nnnRESULTSnPatients with HPT had more psychic complaints (P = .03 to .007) of lassitude, fatigue, irritability, and lack of sexual and emotional interests. They had lower bone density in total body, spine, and hip (P = .008 to .0004) and higher serum alkaline phosphatase, cholesterol (very-low-density lipoprotein), triglycerides (total, very-low-density lipoprotein), glucose, urate, and hemoglobin values (P = .02 to .0001). Patients visited physicians more often (P = .008) and had more antihypertensive therapy (P = .02).nnnCONCLUSIONSnMild, asymptomatic HPT in patients unaware of their disorder displays significant psychic symptoms, bone loss, and risk factors of cardiovascular disease.

Persistent nightmares are associated with repeat suicide attempt A prospective study

The aim of this prospective study was to determine if sleep disturbances and nightmares are associated with increased risk of repeat suicide attempt. Patients (n=165) aged 18-68 years who were admitted to medical or psychiatric wards after a suicide attempt completed an initial interview; 98 of these took part in a 2-month follow-up interview. The Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) and two self-report instruments, the Uppsala Sleep Inventory and the Comprehensive Psychopathological Rating Scale (CPRS) Self-Rating Scale for Affective Syndromes, were administered both at baseline and follow-up. Data concerning repeat suicide attempts within 2 years were obtained from hospital records. Analyses were performed using Students t-test, chi-square test, and logistic regression. In total 42 patients (26%) made at least one repeat suicide attempt within 2 years. While neither difficulties initiating/maintaining sleep nor early morning awakening at baseline predicted repeat attempt, having frequent nightmares did (OR=3.15). The risk was further heightened when nightmares were reported at both baseline and 2-month follow-up (OR=5.20). These associations remained after adjusting for sex, axis-I DSM-IV diagnoses, and self-reported depression and anxiety symptom intensity. Our findings suggest that nightmares might constitute a marker for increased risk of suicidal behavior.

Psychiatric morbidity in primary hyperparathyroidism

AbstractThis report deals with the psychiatric symptomatology in patients with primary hyperparathyroidism (HPT). In a retrospective search of hospital records, psychiatric symptoms were found in 102 (23%) of 441 patients, 78 of whom had depressive and anxiety states. The presence of psychiatric symptoms was not related to the degree of hypercalcemia. Screening for HPT in 101 old patients hospitalized at a psychogeriatric clinic revealed HPT in 5 (5%) patients. Among 13 patients with organic brain syndrome (e.g., senile dementia) and HPT, 8 patients (with a duration of psychiatric illness of less than 2 years) improved mentally after parathyroid surgery, and could return home or to somatic units. The psychiatric symptomatology was prospectively investigated in 59 consecutive patients with primary HPT (mean serum calcium, 2.89±0.30 mmol/l), using the Comprehensive Psychopathological Rating Scale (CPRS). A majority of the patients had considerable psychiatric symptoms (mean CPRS total score, 13.7±9.1) compared with a healthy control group (mean CPRS total score, 4.4±2.0;p <0.001). The most pronounced psychiatric symptoms among the patients were fatiguability, lassitude, failing memory, concentration difficulties, sadness, and inner tension. Analysis of monoamine metabolites in the cerebrospinal fluid in 48 of the patients revealed subnormal values of 5-hydroxyindoleaceticacid (5-HIAA) and homovanillic acid (HVA). At follow-up, 1–1 1/2 years after parathyroid surgery, there was a marked improvement in mental health in the patients (p <0.001), together with a significant rise in the levels of 5-HIAA and HVA (p <0.05).nOur findings demonstrate that psychiatric symptoms are present in a majority of patients with primary HPT, that the symptoms are reversed by parathyroid surgery, and that their severity seems not to be related to the degree of hypercalcemia. The results also indicate that HPT is associated with changes in the central nervous system turnover of monoamines, of possible importance for the symptomatology.RésuméCette étude rétrospective traite la Symptomatologie psychiatrique des patients présentant un hyperparathyroïdisme primitif (HPT). Cent deux patients (23%) sur 441, dont 78 étaient soit en état dépressif ou anxieux, présentaient une Symptomatologie psychiatrique. Limportance des désordres psychiatriques nétait pas en rapport avec lhypercalcémie. Le dépistage systématique chez 101 patients ágés hospitalisés dans une clinique de psychogériatrie, a révélé 5 patients (5%) qui avaient un HPT. Sur 13 patients présentant un syndrome cérébral organique (démence sénile, par exemple) et HPT, 8 patients (pour lesquels la maladie psychiatrique avait duré moins de 2 ans) ont été améliorés sur le plan mental à la suite de la chirurgie et ont pu réintégrer leur foyer ou leur service dhospitalisation non psychiatrique. La Symptomatologie psychiatrique a ensuite été évaluée prospectivement chez 59 patients consécutifs ayant un HPT primitif (calcémie moyenne, 2.89±0.30 mmol/l) par le système CPRS (Comprehensive Psychopathological Rating Scale). La majorité des patients avait une Symptomatologie psychiatrique (score CPRS moyen, 13,7±9.1) comparé au groupe non psychiatrique (score moyen, 4.4±2.0;p < 0.001). Les symptomes les plus fréquents étaient: fatigabilité, lassitude, mémoire défaillante, difficulté de concentration, tristesse et tension intern. Le dosage des métabolites monoamines dans le liquide céphalorachidien chez 48 de ces patients a montré des valeurs subnormales de 5-HIAA et dAHV. Létat mental des patients un an à un an et demi après chirurgie parathyroïdienne était nettement meilleure (p < 0.001). De même, les taux de 5-HIAA et dAHV avaient augmenté (p < 0.05).Nos résultats montrent que la Symptomatologie psychiatrique: (a) est fréquente chez le patient avec un HPT primitif, (b) est curable par la chirurgie, et (c) nest pas proportionnelle à lhypercalcémie. Nos résultats prouvent aussi que le HPT est associé à des modifications du renouvellement des monoamines dans le système nerveux central, expliquant la possibilité de Symptomatologie neurologique.ResumenEl presente informe se refiere a la sintomatología psiquiátrica en pacientes con hiperparatiroidismo primario (HPT). En un estudio retrospectivo sobre historias clínicas hospitalarias se hallaron síntomas psiquiátricos en 102 (23%) de 441 pacientes, 78 de los cuales tenían estados depresivos y de ansiedad. La presencia de síntomas psiquiátricos no aparecio relacionada con el grado de hipercalcemia. Un tamizaje para detectar HPT en 101 pacientes ancianos hospitalizados en una clínica psiquiátrica reveló HPT en 5 casos (5%). Entre 13 pacientes con sindrome cerebral orgánico (e.g., demencia senil) y HPT, 8 pacientes (con evolución de su enfermedad psiquiátrica de menos de 2 años) exhibieron mejoría mental después de cirugía paratiroidea, y les fue posible retornar a su hogar o a unidades somáticas. La sintomatología psiquiátrica fue investigada en forma prospectiva en 59 pacientes consecutivos con HPT primario (calcio sérico promedio, 2.89±0.30 mmol/l), mediante la aplicación de la Escala de Valoración Psicopatológica Comprensiva (EVPC). La mayoría de los pacientes présentó considerable sintomatología psiquiátrica (el valor promedio del puntaje total según la EVPC fue 13.7±9.1) en comparación con un grupo control sano (el valor promedio del puntaje según EVPC fue 4.4±2.0,p < 0.001). Los síntomas más prominentes en estos pacientes fueron fatigabilidad, lasitud, falla de memoria, dificultades de concentración, tristeza, y tensión interior. El análisis de los metabolitos de las monoaminas en el líquido cefalorraqufdeo en 48 de los pacientes reveló valores subnormales de ácido 5-hidroxiindolacético (5-HIAA) y ácido hemovalínico (HVA). En el seguimiento 1–1 1/2 anos después de efectuada la cirugía paratiroidea se observó una marcada mejoría en el estado de salud mental en los pacientes (p < 0.001) junto con un aumento significativo en los niveles de 5-HIAA y HVA (p < 0.05).Nuestros hallazgos demuestran que los síntomas psiquiátricos se encuentran en la mayoría de los pacientes con HPT primario, que los síntomas pueden ser revertidos con la cirugía paratiroidea, y que la severidad de la sintomatología no se relaciona con el grado de hipercalcemia. Los resultados también indican que el HPT está asociado con alteraciones en el recambio de monoaminas en el sistema nervioso central, lo cual posiblemente es de importancia en cuanto a la sintomatología.

CEREBROSPINAL FLUID CALCIUM, PARATHYROID HORMONE, AND MONOAMINE AND PURINE METABOLITES AND THE BLOOD-BRAIN BARRIER FUNCTION IN PRIMARY HYPERPARATHYROIDISM

Psychiatric disturbances are common in primary hyperparathyroidism (HPT), but their pathogenesis is essentially unknown. This study deals with cerebrospinal fluid (CSF) calcium homeostasis and its connection with parathyroid hormone (PTH), blood-brain barrier (BBB) function, and central monoamine and purine metabolites in patients with primary HPT. In 22 patients with primary HPT (serum calcium 2.85 +/- 0.21 mmol/l), the CSF concentrations of total and ionized calcium were higher (1.21 +/- 0.08 mmol/l, p less than 0.01, and 1.09 +/- 0.05 mmol/l, p less than 0.001, respectively) than in 11 normocalcemic reference subjects. The values correlated with serum calcium concentration (p less than 0.001) and CSF/serum albumin ratio, a measure of BBB permeability. The latter ratio was elevated in one-third of the patients with HPT, indicating BBB damage. CSF immunoreactive intact PTH was higher in the HPT patients than in the reference group (p less than 0.05), and serum and CSF PTH were positively correlated (p less than 0.05). The CSF levels of the monoamine metabolites 5-hydroxyindoleacetic acid (5HIAA) and homovanillic acid (HVA) were lower, and the level of urate in CSF was higher, in the HPT patients than in the reference subjects, while there were no consistent differences in CSF hypoxanthine or xanthine. CSF 5HIAA correlated inversely with CSF ionized calcium (r = -0.42, p = 0.02). After parathyroid surgery, CSF calcium and urate decreased significantly and CSF monoamine metabolites increased slightly. The decrease in CSF ionized calcium correlated with the alleviation of psychiatric symptoms. The results indicate the importance of increased CSF calcium concentrations in patients with primary HPT and suggest a relation between central calcium regulation and central turnover of monoamines.

Psychiatric symptoms and cerebrospinal fluid monoamine metabolites in primary hyperparathyroidism

This prospective study included 32 patients with primary hyperparathyroidism (HPT). As compared with a healthy reference group, the patients had pronounced psychiatric symptomatology [CPRS score 17.2 +/- 9.0 (SD) versus 4.4 +/- 2.0], which was mainly affective in character. The severity of symptoms was not related to the serum calcium or parathyroid hormone concentrations. The majority of the patients had low CSF concentrations of monoamine metabolites (5-HIAA, HVA, and MHPG) and, in particular, those with the most severe psychiatric symptoms had low values for 5-HIAA. At follow-up, 1 year after parathyroid surgery, the patients displayed a clear improvement in mental health (CPRS score 4.4 +/- 3.0) together with an increase in CSF concentrations of 5-HIAA and HVA. The study demonstrates that significant psychiatric disturbances, which can be improved/normalized by surgery, are common in patients with HPT and are possibly related to changes in the central nervous system turnover of monoamines.

Is usage of hypnotics associated with mortality

OBJECTIVEnTo investigate the influence of hypnotic usage on all-cause and cause-specific mortality in a middle-aged population.nnnMETHODSnA cohort of 1750 men and 1773 women aged 30-65 years who responded to a postal questionnaire in 1983. The questionnaire included questions about hypnotic usage, sleep duration, sleep complaints, medical conditions, depression, demographic and life style variables. Mortality data for the period 1983-2003 were collected.nnnRESULTSnRegular hypnotic usage was reported by 1.7% of men and 2.2% of women, and was associated with short sleep, sleeping difficulties, several health problems and depression. During the 20-year follow-up period 379 men (21.5%) and 278 women (15.5%) died. After adjustment for potential risk factors in multivariate analyses regular hypnotic usage was associated with significantly increased risk of all-cause mortality in men (Hazard ratios [HR], 4.54; 95% confidence interval [CI], 2.47-8.37) and in women 2.03 (95% CI, 1.07-3.86). With regard to cause-specific mortality, regular hypnotic usage in men was a risk factor for coronary artery disease death, cancer death, suicide and death from all remaining causes. In women it was a risk factor for suicide.nnnCONCLUSIONSnOur results show an increased risk of all-cause mortality and cause-specific mortality in regular users of hypnotics.

Valproic Acid Phase Shifts the Rhythmic Expression of PERIOD2::LUCIFERASE

Valproic acid (VPA) is an anticonvulsant used to treat bipolar disorder, a psychiatric disease associated with disturbances in circadian rhythmicity. Little is known about how VPA affects circadian rhythms. The authors cultured tissues containing the master brain pacemaker for circadian rhythmicity, the suprachiasmatic nuclei (SCN), and skin fibroblasts from transgenic PERIOD2::LUCIFERASE (PER2::LUC) mice and studied the effect of VPA on the circadian PER2::LUC rhythm by measuring bioluminescence. VPA (1 mM) significantly phase advanced the PER2::LUC rhythm when applied at a time point corresponding to the lowest (trough, ~ZT 0) PER2::LUC expression but phase delayed the PER2::LUC rhythm when the drug was administered at the time of highest (peak, ~ZT 12) protein expression. In addition, it significantly increased the overall amplitude of PER2::LUC oscillations at time points at or close to ZT 12 but had no effect on period. Real-time PCR analyses on mouse and human fibroblasts revealed that expressions of other clock genes were increased after 2 h treatment with VPA. Because VPA is known to inhibit histone deacetylation, the authors treated cultures with an established histone deacetylation inhibitor, trichostatin A (TSA; 20 ng/mL), to compare the effect of VPA and TSA on molecular rhythmicity. They found that TSA had similar effects on the PER2::LUC rhythm as VPA. Furthermore, VPA and TSA significantly increased acetylation on histone H3 but in comparison little on histone H4. Lithium is another commonly used treatment for bipolar disorder. Therefore, the authors also studied the impact of lithium chloride (LiCl; 10 mM) on the PER2::LUC rhythm. LiCl delayed the phase, but in contrast to VPA and TSA, LiCl lengthened the PER2::LUC period and had no effect on histone acetylation. These results demonstrate that VPA can delay or advance the phase, as well as increase the amplitude, of the PERIOD2::LUCIFERASE rhythm depending on the circadian time of application. Furthermore, the authors show that LiCl delays the phase and lengthens the period of the PER2::LUC rhythm, confirming previous reports on circadian lithium effects. These different molecular effects may underlie differential chronotherapeutic effects of VPA and lithium.

Psychiatric Symptomatology in Patients with Primary Hyperparathyroidism

A retrospective investigation was made of the occurrence of psychiatric symptoms among 441 patients operated on for primary hyperparathyroidism in Uppsala in 1956-79, and of the relationship between such symptoms and age, sex and degree of hypercalcaemia. A follow-up, using a mailed questionnaire, was carried out 4-27 years postoperatively. Psychiatric symptoms were found in 23% of the patients (102/441). The patients with these symptoms had the same sex distribution and serum calcium levels as the other patients, but were significantly older. Severe symptoms occurred more frequently in older patients. Such symptoms were noted not only in patients with very high serum calcium values but also in association with mild or moderate hypercalcaemia. The most common symptoms were depressive and anxiety states, which occurred in 78 patients. Psychosis with hallucinations and paranoid ideas was found in four patients. Eight patients had an organic brain syndrome and a further 12 patients had minor cerebral impairment. At the follow-up half of the patients reported an improvement after the first postoperative year. Most of them considered that this improvement was sustained at the time of follow-up. This study indicates that psychiatric symptoms are common among patients with hyperparathyroidism and can occur even with moderate hypercalcaemia. Elderly patients seem to be more vulnerable and more often develop severe symptoms such as psychosis or organic brain syndrome.

Activation of kynurenine pathway in ex vivo fibroblasts from patients with bipolar disorder or schizophrenia: Cytokine challenge increases production of 3-hydroxykynurenine

Accumulating data suggest a causative link between immune stimulation, disturbed metabolism of tryptophan, and pathogenesis of bipolar disorder and schizophrenia. The goal of this study was to examine the production of kynurenic acid (KYNA), 3-hydroxykynurenine (3-HK) and the expression of kynurenine pathway enzymes involved in their synthesis and metabolism in cultured skin fibroblasts obtained from patients with bipolar disorder, schizophrenia or from healthy control individuals. The assessment was performed under basal conditions or following treatment with interferon (IFN)-γ, tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, or their combinations, in cells exposed to exogenous kynurenine. In both groups of patients, the baseline production of KYNA and 3-HK was increased, as compared to control subjects. Case-treatment analyses revealed significant interactions between bipolar case status and IL-1β, IL-6, IFN-γ + TNF-α, or IFN-γ + IL-1β, as well as between schizophrenia case status and IL-1β, IFN-γ + TNF-α, or IFN-γ + IL-1β, in terms of higher 3-HK. Noteworthy, no case-treatment interactions in terms of KYNA production were found. Observed changes did not appear to correlate with the expression of genes encoding kynurenine aminotransferases (KATs), kynureninase (KYNU) or kynurenine-3-monooxygenase (KMO). The single nucleotide polymorphisms (SNPs), rs1053230 and rs2275163, in KMO influenced KYNA levels yet did not explain the case-treatment discrepancies. In conclusion, our present findings indicate the utility of skin-derived fibroblasts for kynurenines research and support the concept of kynurenine pathway alterations in bipolar disorder and schizophrenia. The increase in ratio between neurotoxic 3-HK and neuroinhibitory/neuroprotective KYNA following exposure to cytokines may account for altered neurogenesis and structural abnormalities characteristic for both diseases.

The Minimal Insomnia Symptom Scale (MISS) : A Brief Measure of Sleeping Difficulties

To evaluate basic psychometric properties and obtain normative values for a novel 3-item scale, the Minimal Insomnia Symptom Scale (MISS), a sleep questionnaire was sent out to a randomly selected sample of the general population, aged 20-64 years. Responses were obtained from 1075 subjects corresponding to a response rate of 78%. Results showed that MISS possessed satisfactory reliability and validity. Women scored significantly higher than men while there was no age relationship. A receiver operating characteristic curve analysis revealed that MISS was able to distinguish subjects with a clinical insomnia according to ICD-10 research criteria. The main advantage of MISS over other insomnia instruments is its brevity and ease of use. Evidence was provided for the utility of MISS in epidemiological settings. MISS also showed promise as a convenient ultra-short screening measure of insomnia in health care settings.