Aripiprazole Augmentation to Mood Stabilizers for Obsessive-Compulsive Symptoms in Bipolar Disorder.

Background and objectives: Aripiprazole is a first-line agent in the treatment of bipolar disorder (BD) and available data demonstrates its efficacy on clinical symptoms in serotonin reuptake inhibitors-resistant obsessive-compulsive disorder (OCD) patients. Therefore, aripiprazole augmentation to mood stabilizers could represent a promising treatment in BD patients with comorbid OCD. The study examined the efficacy and safety of aripiprazole added to lithium or valproate for the treatment of obsessive-compulsive (OC) symptoms in euthymic BD patients with comorbid OCD. Materials and methods: This is a 12-week prospective observational study. The efficacy of aripiprazole on OC symptoms was assessed through the mean change of Yale-Brown Obsessive-Compulsive (YBOCS) total score. Tolerability was assessed with the Utvalg for Kliniske Undersogelser (UKU) side effect scale and by reporting adverse events. Results: A total of 70 patients were included in the analyses. The withdrawal rate was 21.4%, mainly due to adverse events. Mean ± SD final aripiprazole dose was 15.2 ± 5.3 in the completer sample (N = 55). The Y-BOCS mean score decreased from 24.0 ± 4.1 at baseline to 17.1 ± 4.3 at 12 weeks. Treatment response rate (Y-BOCS reduction ≥ 35%) was 41.8%, while partial response rate (Y-BOCS reduction greater than 25% but less than 35% from baseline) accounted for the other 18.2% of patients. Overall, 91.4% of completers had at least 1 adverse effect (tremor, tension/inner unrest, reduced duration of sleep, akathisia). No significant differences emerged comparing aripiprazole efficacy and tolerability between patients treated with lithium or valproate. Conclusion: Our findings show that aripiprazole addition to lithium or valproate can reduce OC symptoms in real-world BD euthymic patients.

155Tb production by cyclotrons: what level of 155Gd enrichment allows clinical applications?

BACKGROUND: 155Tb represents a potentially useful radionuclide for diagnostic medical applications, but its production remains a challenging problem, in spite of the fact that many production routes have been already investigated and tested. A recent experimental campaign, conducted with low-energy proton beams impinging on a 155Gd target with 91.9% enrichment, demonstrated a significant co-production of 156gTb, a contaminant of great concern since its half-life is comparable to that of 155Tb and its high-energy γ emissions severely impact on the dose released and on the quality of the SPECT images. In the present investigation, the isotopic purity of the enriched 155Gd target necessary to minimize the co-production of contaminant radioisotopes, in particular 156gTb, was explored using various computational simulations. RESULTS: Starting from the recent experimental data obtained with a 91.9% 155Gd-enriched target, the co-production of other Tb radioisotopes besides 155Tb has been theoretically evaluated using the Talys code. It was found that 156Gd, with an isotopic content of 5.87%, was the principal contributor to the co-production of 156gTb. The analysis also demonstrated that the maximum amount of 156Gd admissible for 155Tb production with a radionuclidic purity higher than 99% was 1%. A less stringent condition was obtained through computational dosimetry analysis, suggesting that a 2% content of 156Gd in the target can be tolerated to limit the dose increase to the patient below the 10% limit. Moreover, it has been demonstrated that the imaging properties of the produced 155Tb are not severely affected by this level of impurity in the target. CONCLUSIONS: 155Tb can be produced with a quality suitable for medical applications using low-energy proton beams and 155Gd-enriched targets, if the 156Gd impurity content does not exceed 2%. Under these conditions, the dose increase due to the presence of contaminant radioisotopes remains below the 10% limit and good quality images, comparable to those of 111In, are guaranteed.

The innovative 52g Mn for positron emission tomography (PET) imaging: Production cross section modeling and dosimetric evaluation.

BACKGROUND: Manganese is a paramagnetic element suitable for magnetic resonance imaging (MRI) of neuronal function. However, high concentrations of Mn2 + can be neurotoxic. 52g Mn may be a valid alternative as positron emission tomography (PET) imaging agent, to obtain information similar to that delivered by MRI but using trace levels of Mn2 + , thus reducing its toxicity. Recently, the reaction n a t $^{nat}$ V(α,x)52g Mn has been proposed as a possible alternative to the standard n a t $^{nat}$ Cr(p,x)52g Mn one, but improvements in the modeling were needed to better compare the two production routes. PURPOSE: This work focuses on the development of precise simulations and models to compare the 52g Mn production from both reactions in terms of amount of activity and radionuclidic purity (RNP), as well as in terms of dose increase (DI) due to the co-produced radioactive contaminants, versus pure 52g MnCl2 . METHODS: The nuclear code Talys has been employed to optimize the n a t $^{nat}$ V(α,x)52g Mn cross section by tuning the parameters of the microscopic level densities. Thick-target yields have been calculated from the expression of the rates as energy convolution of cross sections and stopping powers, and finally integrating the time evolution of the relevant decay chains. Dosimetric assessments of [ x x $^{xx}$ Mn]Cl2 have been accomplished with OLINDA software 2.2.0 using female and male adult phantoms and biodistribution data for 52g MnCl2 in normal mice. At the end, the yield of x x $^{xx}$ Mn radioisotopes estimated for the two production routes have been combined with the dosimetric results, to assess the DI at different times after the end of the irradiation. RESULTS: Good agreement was obtained between cross-section calculations and measurements. The comparison of the two reaction channels suggests that n a t $^{nat}$ V(α,x)52g Mn leads to higher yield and higher purity, resulting in more favorable radiation dosimetry for patients. CONCLUSIONS: Both n a t $^{nat}$ V(α,x) and n a t $^{nat}$ Cr(p,x) production routes provide clinically acceptable 52g MnCl2 for PET imaging. However, the n a t $^{nat}$ V(α,x)52g Mn reaction provides a DI systematically lower than the one obtainable with n a t $^{nat}$ Cr(p,x)52g Mn and a longer time window in which it can be used clinically (RNP ≥ 99%).

[Combined treatments in obsessive-compulsive disorder: current knowledge and future prospects]. / L'integrazione dei trattamenti nel disturbo ossessivo-compulsivo: conoscenze attuali e prospettive future.

AIM: Serotonin reuptake inhibitors (SRIs) and/or cognitive-behavioral psychotherapy (CBT) are first-line treatments for obsessive-compulsive disorder (OCD). The study discuss whether: a) combining both treatments ab initio is more effective than either monotherapy alone; and b) a sequential treatment is effective both in responder and non responder patients. METHODS: Have been carried out a search on Medline/PubMed database, selecting clinical randomized controlled studies in English. Have been examined 9 randomized controlled studies where combined treatment ab initio was compared to CBT alone, and 6 where combination treatment was compared to SRI alone. No controlled studies were found for sequential treatments in OCD. Have been then examined naturalistic studies, 2 including responder patients and 7 including non responder patients. RESULTS: Of the 9 studies, 7 didn't find any additional benefit of combining treatments as compared to CBT alone; in 1 study the combination strategy resulted more effective than CBT alone in children and adolescents, and in another in severely depressed adult patients with OCD. As compared to SRIs alone, combining treatments was not more effective in 4 studies, while in 2 studies it was more effective. All studies concerning sequential treatments found evidence of efficacy of this strategy. DISCUSSION: Combining ab initio CBT and SRI has not been found to be clearly superior of either therapy alone, except for patients with severe depression and for children and adolescents. On the contrary, a sequential strategy may be used successfully both to treat residual symptoms in responders and to determine clinical response in resistant patients.

Duration of untreated illness and response to SRI treatment in Obsessive-Compulsive Disorder.

BACKGROUND: The duration of untreated illness (DUI) is a potentially modifiable parameter associated with worst prognosis in several psychiatric disorders, but poorly investigated in Obsessive-Compulsive Disorder (OCD). Our aims were to estimate the mean DUI in a large sample of individuals with OCD and its impact on response to the first ever adequate SRI treatment. METHODS: We retrospectively examined records of 251 patients with OCD (SCID-I, DSM-IV) who referred to our Department and were prospectively and naturalistically treated according to International Guidelines. The DUI was defined as the interval between age at onset and age at which patients received their first adequate pharmacological treatment. Response rates were compared in subjects with brief (≤24 months) versus long DUI. Logistic regression models predicting response and 12-week Y-BOCS score were run with DUI (among others) as independent variable. RESULTS: The mean DUI was 106.19 ± 118.14 months, with a mean interval between onset of the disorder and when patients sought professional help of 82.27 ± 112.30 months. Response rates were significantly reduced in subjects with a long DUI, using both the cut-off of 24 months and the median value of 60 months. Regression analyses confirmed that a long (>24 months) DUI predicts poorer response and higher Y-BOCS scores at 12 weeks. CONCLUSIONS: Our results, although preliminary, seem to suggest that a longer duration of untreated illness in OCD is associated with poorer outcome in terms of response to SRI treatments. It is imperative to do all the possible to shorten the DUI, both by improving access to mental health services, improving the ability of primary care physicians and mental health professionals to recognize OCD, and disseminate best-practice prescription guidelines.

Increased uric acid levels in bipolar disorder subjects during different phases of illness.

BACKGROUND: Recent evidence indicates the possible involvement of adenosine and the purinergic system in the pathophysiology of bipolar disorder (BD). The aim of this study is to compare serum uric acid (UA) levels in a large group of BD patients (in mania, depression and euthymia) vs. a control group of patients with different psychiatric disorders. METHODS: 150 BD (SCID-I; DSM-IV) patients were compared to 150 age- and gender-matched subjects with MDD, OCD, or Schizophrenia. Mean serum UA values were compared with the ANOVA, with Bonferroni's post-hoc tests. RESULTS: Mean serum UA levels (5.06 ± 1.45 vs. 4.17 ± 1.05 mg/dL) and rates of hyperuricaemia (30.7% vs. 6.7%) were significantly higher in the bipolar than in the control group. No differences were detected between bipolars in different phases of illness, with all three groups (manic, depressive and euthymic bipolars) showing significantly higher UA levels as compared to controls. No correlations were found between UA levels and YMRS or HAM-D scores. Mean UA levels were also higher in bipolars never exposed to mood stabilizers vs. controls (5.08 ± 1.43 vs. 4.17 ± 1.05 mg/dL), with no differences compared to other bipolars. LIMITATIONS: Our study suffers from the lack of a healthy comparison group; moreover, longitudinal data are missing. CONCLUSIONS: Our study provides further evidence of a purinergic dysfunction associated with BD, in all phases of the illness. It is possible that increased UA levels are a trait marker of higher vulnerability to bipolar disorder, and are even more increased during mania (mostly in the first manic episode of drug-naïve patients).

Effects of maintenance lithium treatment on serum parathyroid hormone and calcium levels: a retrospective longitudinal naturalistic study.

OBJECTIVE: The aim of this retrospective longitudinal naturalistic study was to evaluate the effects of maintenance lithium treatment on parathyroid hormone (PTH) and calcium levels. METHODS: A retrospective longitudinal naturalistic study design was used. Data were collected from the database of a tertiary psychiatric center covering the years 2010-2014. Included were bipolar patients who had never been exposed to lithium and had lithium started, and who had PTH, and total and ionized calcium levels available before and during lithium treatment. Paired t-tests were used to analyze changes in PTH and calcium levels. Linear regressions were performed, with mean lithium level and duration of lithium exposure as independent variables and change in PTH levels as dependent variable. RESULTS: A total 31 patients were included. The mean duration of lithium treatment was 18.6±11.4 months. PTH levels significantly increased during lithium treatment (+13.55±14.20 pg/mL); the rate of hyperparathyroidism was 12.9%. Neither total nor ionized calcium increased from baseline to follow-up; none of our patients developed hypercalcemia. Linear regressions analyses did not show an effect of duration of lithium exposure or mean lithium level on PTH levels. CONCLUSION: Lithium-associated stimulation of parathyroid function is more common than assumed to date. Among parameters to be evaluated prior to lithium implementation, calcium and PTH should be added.

Lithium-associated hyperparathyroidism and hypercalcaemia: a case-control cross-sectional study.

BACKGROUND: Lithium is recommended as a first-line treatment for Bipolar Disorder (BD). Thyroid and renal alterations are well known lithium side-effects, while effects on parathyroids are less studied. The aim of this case-control cross-sectional study is to compare parathyroid hormone (PTH) and calcium levels in lithium-exposed bipolar patients and in subjects who had never been exposed to lithium. METHODS: 112 BD patients were enrolled, 58 on lithium since at least 1 month (mean exposure 60.8 ± 74.8 months) and 54 in the control group. Blood exams included complete blood count, PTH, total and ionized calcium, TSH, T3 and T4, creatinine, urea, sodium and potassium, and lithium serum levels. The Student's t-test and the Pearson's Chi-square test were used for bivariate analyses. A linear regression model was used to analyze the relationship between the duration of exposure to lithium and PTH and calcium levels. RESULTS: PTH and ionized calcium levels were significantly higher in lithium-exposed patients; the proportions of subjects with hyperparathyroidism (8.6%) and hypercalcaemia (24.1%) were significantly greater in lithium-exposed patients. The linear regression analyses showed a significant effect of exposure to lithium in months on ionized calcium levels but not on PTH levels. LIMITATIONS: Given the cross-sectional design of the study we could not identify the exact time of occurrence of hyperparathyroidism. CONCLUSIONS: Our results indicate that lithium-associated stimulation of parathyroid function is more common than assumed to date. Among parameters to be evaluated prior to lithium implementation and during long-term lithium maintenance, calcium (and eventually PTH) should be added.