Impacto presupuestario de XEN®63 en el tratamiento del glaucoma primario de ángulo abierto en España / Budget impact analysis of the XEN®63 for the treatment of primary open angle glaucoma in Spain

Antecedentes y objetivo Evaluar el impacto económico en España derivado de la introducción del implante XEN®63 como alternativa quirúrgica en el manejo del glaucoma primario de ángulo abierto (GPAA) con o sin cataratas en pacientes refractarios. Materiales y métodos Se diseñó un análisis de impacto presupuestario para estimar los costes del tratamiento quirúrgico del GPAA desde la perspectiva del Sistema Nacional de Salud (SNS) español, en un horizonte temporal de1 año. Los comparadores considerados (trabeculectomía, esclerectomía profunda no perforante, válvula de Ahmed, iStent inject®, Preserflo® microshunt y XEN®45) se corresponden a los empleados en la práctica clínica pública española. Para el cálculo de la población diana, cuotas de mercado y uso de recursos en términos de visitas de seguimiento, procedimientos adicionales y complicaciones poscirugía, se emplearon datos de la literatura y se validaron con un panel de cuatro expertos. Los costes unitarios (€de2021) se obtuvieron de la base de datos ESALUD Resultados la inclusión de XEN®63 podría generar un ahorro de 2.569.737€ tras un año desde su introducción, derivado del ahorro en el coste del implante y del procedimiento (−423.120; −0,7%), de las visitas de seguimiento (−777.407€; −4,5%), de los procedimientos adicionales (−1.048.145€, −20,6%) y de las complicaciones poscirugía (−321.065€, −14,2%). Conclusiones La incorporación de XEN®63 en el arsenal quirúrgico para el tratamiento del GPAA refractario con y sin cataratas podría generar ahorros para el SNS (AU)

Background and objective To evaluate the economic impact in Spain derived from the introduction of the XEN®63 implant as a surgical alternative in the management of primary open angle glaucoma (POAG) with or without cataract in refractory patients. Materials and methods A budget impact analysis was designed to estimate the costs of surgical treatment of POAG from the perspective of the Spanish National Health System (NHS), over a time horizon of 1year. The comparators considered (trabeculectomy, deep non-perforating sclerectomy, Ahmed valve, iStent inject®, Preserflo® microshunt and XEN®45) correspond to those used in Spanish public clinical practice. For the calculation of the target population, market shares and resource use in terms of follow-up visits, additional procedures and post-surgery complications, data from the literature were used and validated with a panel of 4 experts. Unit costs (€2021) were obtained from the ESALUD database. Result The inclusion of XEN®63 could generate savings of €2,569,737 after one year since its introduction, derived from savings in the cost of the implant and procedure (−€423,120; −0.7%), follow-up visits (−€777,407; −4.5%), additional procedures (−1,048,145; −20.6%) and post-surgery complications (−€321,065; −14.2%). Conclusion The incorporation of XEN®63 in the surgical arsenal for the treatment of refractory POAG with and without cataracts could generate savings for the NHS (AU)

Budget impact analysis of the XEN®63 for the treatment of primary openangle glaucoma in Spain.

BACKGROUND AND OBJECTIVE: To evaluate the economic impact in Spain derived from the introduction of the XEN®63 implant as a surgical alternative in the management of primary open angle glaucoma (POAG) with or without cataract in refractory patients. MATERIALS AND METHODS: A budget impact analysis was designed to estimate the costs of surgical treatment of POAG from the perspective of the Spanish National Health System (NHS), over a time horizon of 1 year. The comparators considered (trabeculectomy, deep non-penetrating sclerectomy, Ahmed valve, iStent inject, Preserflo® microshunt and XEN®45) correspond to those used in Spanish public clinical practice. For the calculation of the target population, market shares and resource use in terms of follow-up visits, additional procedures and post-surgery complications, data from the literature were used and validated with a panel of 4 experts. Unit costs (€ 2021) were obtained from the ESALUD database. RESULTS: The inclusion of XEN®63 could generate savings of €2,569,737 after one year since its introduction, derived from savings in the cost of the implant and procedure (-€423,120; -0.7%), follow-up visits (-€777,407; -4.5%), additional procedures (-€1,048,145; -20.6%) and post-surgery complications (-€321,065; -14.2%). CONCLUSIONS: The incorporation of XEN63®in the surgical arsenal for the treatment of refractory POAG with and without cataracts could generate savings for the NHS.

Cementoplasty in the management of painful extraspinal bone metastases: our experience.

PURPOSE: The aim of this study was to demonstrate the effectiveness of interventional techniques in the palliative management of painful extraspinal bone metastases. MATERIALS AND METHODS: Cementoplasty alone or in combination with radiofrequency (RF) ablation was performed in 14 skeletal extravertebral segments in 13 patients with ages ranging from 50 to 74 (average 67) years. The primary tumours were myeloma (n=5), renal carcinoma (n=5), hepatocellular carcinoma (n=2) and bladder carcinoma (n=2). Metastases were located at the acetabulum (n=4), femur (n=5), humerus (n=1), scapula (n=2) and iliac bone (n=2). The clinical indication was a pain intensity score >4 on the visual analogue scale (VAS) partially or totally refractory to analgesic medication. Clinical evaluation was based on clinical and neurological conditions before and immediately after the procedure and during the follow-up. RESULTS: Technical success was achieved in all cases. Ten patients were treated by cementoplasty alone and four cases by cementoplasty combined with RF ablation. After treatment, all patients experienced improved symptoms, as demonstrated by the VAS score, which remained constant during follow-up. All patients were followed for between 2 and 14 (average 6.1) months. We had one major complication in a patient who developed an abscess, which was treated by percutaneous drainage. CONCLUSIONS: In our experience, cementoplasty alone for small lesions or combined with RF ablation in larger lesions is an effective and safe therapy in the palliative management of painful extraspinal bone metastases.

Quetiapine and classical mood stabilizers in the long-term treatment of Bipolar Disorder: a 4-year follow-up naturalistic study.

BACKGROUND: The aim of this naturalistic study was to compare the effectiveness of quetiapine and classical mood stabilizers, as mono- or combination therapy, in the long-term treatment of Bipolar Disorder (BD). METHODS: 232 DSM-IV BD I (n=91) or BD II (n=141) patients, treated and followed up for four years, were studied. Mood stabilizers were chosen by the treating psychiatrists on the basis of their clinical judgement. The sample was subdivided into 6 treatment groups: quetiapine (n=41), lithium (n=39), sodium valproate (n=73), lamotrigine (n=31), quetiapine plus lithium (n=25), and quetiapine plus sodium valproate (n=23). Throughout the 4-year follow-up period patients were assessed monthly, or whenever a recurrence occurred, by the administration of HAMD-21 and of the YMRS. Primary outcome measures were the duration of euthymia and the cumulative proportion of subjects who maintained euthymia. Kaplan-Meier survival analyses were done to tabulate and compare the differences in survival distributions across the different treatment groups (Log-Rank Mantel-Cox test). RESULTS: The combined treatments with quetiapine plus lithium or sodium valproate were more effective overall in maintaining euthymia, (percentages of patients who maintained euthymia: 29.3% for quetiapine, 46.2% for lithium, 32.9% for sodium valproate, 41.9% lamotrigine, 80% for quetiapine plus lithium, and 78.3% for quetiapine plus sodium valproate). In addition, quetiapine monotherapy was as effective as lithium monotherapy or combination treatment with lithium or sodium valproate in preventing the recurrence of major depressive episodes. LIMITATION: The main limitations of the study are the lack of randomized, controlled conditions and the low doses of quetiapine used. CONCLUSION: If the results from this study will be replicated, there will be important implications for the use of quetiapine in the long-term treatment of BD.

Duration of untreated illness in major depressive disorder: a naturalistic study.

BACKGROUND: Most of the studies on the duration of untreated illness (DUI) as a possible predictor of the clinical outcome and the course have focused on the psychotic disorders. The present naturalistic study was aimed to evaluate the possible relationship between the DUI and some clinical characteristics of a sample of patients with major depressive disorder (MDD). METHODS: Sixty-eight patients with MDD, according to the Diagnostic and Statistical Manual of Mental Disorders, IV Edition, Text Revision (DSM-IV-TR) criteria, followed-up for 4 years, were selected, interviewed and their clinical charts reviewed. The DUI was defined as the interval between the onset of the first major depressive episode and the first adequate antidepressant treatment. The sample was divided in two groups according to a DUI 12 months (n = 23). The main demographic and clinical course variables were compared between the two groups using t-tests or chi-squared tests. RESULTS: Patients with a DUI > 12 months were more frequently women (chi2 = 4.005, p = 0.045), had an earlier onset (t = 2.515, p = 0.014), a longer duration of illness (t = -2.483, p = 0.016), a higher number of recurrences (t = -2.262, p = 0.027) and had more frequently comorbid Axis I disorders with onset later than MDD (chi2 = 5.595, p = 0.05). CONCLUSIONS: These findings suggest that a longer DUI may negatively influence the clinical course of MDD. Further studies on larger samples are warranted to confirm these preliminary results.

Brain serotonin transporter binding in non-depressed patients with Parkinson's disease.

Early post-mortem data suggest that damage to brain serotonin neurones might play a role in some features (e.g., depression) of Parkinson's disease (PD). However, it is not known whether such damage is a typical characteristic of living patients with PD or whether the changes are regionally widespread. To address this question we measured, by positron emission tomography imaging, levels of the brain serotonin transporter (SERT), a marker for serotonin neurones, as inferred from binding of [11C]-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile (DASB), a second generation SERT radioligand, in subcortical and cerebral cortical brain areas of clinically advanced non-depressed (confirmed by structured psychiatric interview) patients with PD. SERT binding levels in PD were lower than those in controls in all examined brain areas, with the changes statistically significant in orbitofrontal cortex (-22%), caudate (-30%), putamen (-26%), and midbrain (-29%). However, only a slight non-significant reduction (-7%) was observed in dorsolateral pre-frontal cortex, an area implicated in major depression. Our imaging data suggests that a modest, regionally widespread loss of brain serotonergic innervation might be a common feature of advanced PD. Further investigation will be required to establish whether SERT binding is more or less decreased in those patients with PD who also have major depressive disorder.

Diagnosis and treatment of obsessive-compulsive disorder and related disorders.

Obsessive-compulsive disorder (OCD) is currently recognised as one of the most common psychiatric disorders as well as one of the most disabling of all medical disorders. Obsessive-compulsive related disorders (OCRDs), often comorbid with OCD, include many distinct psychiatric conditions (i.e. some somatoform disorders, eating disorders, impulse control disorders and some neurological conditions) which have overlapping symptoms and compulsive qualities with OCD. Although effective treatments exist, OCD and related disorders are often underdiagnosed and undertreated. Serotonin reuptake inhibitors (SRIs) and cognitive behavioural therapy (CBT) represent the first-line treatment for OCD and related disorders. However, the time and the doses of the medications used in the treatment of OCD and related disorders differ from those recommended in depressive disorders. In addition, remission is not common for patients with OCD and related disorders in clinical practice, and poor responders as well as refractory cases may benefit from different treatment strategies including integrated treatment, pharmacological augmentation and brain stimulation techniques.

Transcultural differences in suicide attempters: analysis on a high-risk population of patients with schizophrenia or schizoaffective disorder.

The aim of the study was to investigate transcultural differences between schizophrenia spectrum disorder patients who did or did not attempt suicide. DSM-IV schizophrenia (N=609) or schizoaffective disorder (N=371) patients who participated in the multicentre International Suicide Prevention Trial (InterSePT) were studied. Patients were sub-divided into 5 groups according to the different geographical regions of recruitment: North America (NA), Europe (EUR), East Europe (EEUR), South Africa (SAf), and South America (SA). The main lifetime clinical variables were compared, within each group, between attempters and non-attempters. The presence of comorbid substance abuse disorder and smoking was associated with suicide attempts in all the geographical groups considered (NA: chi(1)(2)=7.575, p<0.01 and chi(1)(2)=69.549, p<0.0001; EUR: chi(1)(2)=55.068, p<0.0001, and chi(1)(2)=48.431, p<0.0001; EEUR: chi(1)(2)=164.628, p<0.000, and chi(1)(2)=5.127, p<0.01; SA: chi(1)(2)=30.204, p<0.0001 and chi(1)(2)=11.710, p=0.001) except for SAf. For the other clinical variables various differences were found across the different groups. Variables related to suicide behavior were similar across the five groups investigated, with differences only in the age at the first suicide attempt (earlier in the NA sample) and the number of lifetime suicide attempts (higher in the NA sample). Results from this study show that, while some suicide-related clinical characteristics in schizophrenia patients are consistent worldwide suggesting the influence of stable biological traits, other variables may vary across different geographical areas suggesting environmental influences.

[Radical prostatectomy. A review of our series between 1997-2003]. / Prostatectomía radical. Revisión de nuestra serie en el periodo 1997-2003.

OBJECTIVE: To evaluate the complications and results of our series of 398 radical retropubic prostatectomies as an elective treatment for clinically localized prostate cancer. PATIENTS AND METHODS: Between January 1997 and June 2003, a total of 398 radical retropubic prostatectomies have been performed. Mean age was 63.8 years (45.8-78.2), mean PSA at diagnosis 9.32 ng/ml (0.9-129.7). Mean surgical time was 141.6 minutes (70-280), and mean hospitalization was 6.75 days (2-37). RESULTS: Mean follow-up was 65.18 months. We report as peroperatory complications: rectal injury 1.8%, lymphatic leakage 0.3%, urinary fistula 5%. As delay complications: uretrovesical junction stenosis 6%. We observed 49.1% of patients with positive surgical margins. We don't report any peroperatory death. The overall survival rate is 98.5%, the cancer specific survival rate is 99.75%, and the recurrence-free survival rate is 84.97%. CONCLUSIONS: Radical retropubic prostatectomy is an excellent treatment form for patients with clinically localized prostate cancer. A strict selection of patients candidates is important to obtain good results.

Prostatectomía radical. Revisión de nuestra serie en el periodo 1997-2003 / Radical prostactectomy. A review of our serie between 1997-2003

Objetivos: Analizar los resultados y complicaciones de nuestra serie de 398 casos de prostatectomía radical retropúbica como tratamiento electivo del cáncer de próstata órgano confinado. Material y metodos: Entre enero de 1997 y junio de 2003 hemos realizado un total de 398 prostatectomías radicales. La edad media fue de 63,8 años (45,8-78,2), con una media de PSA al diagnóstico de 9,32 ng/ml (0,9-129,7). La media del tiempo quirúrgico es de 141,6 minutos (70-280), y la media de días de ingreso hospitalario de 6,75 días (2-37).Resultados: El seguimiento medio de nuestra serie ha sido de 65,18 meses. Como complicaciones peroperatorias destacamos: lesión rectal 1,8%, linforrea 0,3%, fístula urinaria 5%. Como complicaciones tardías: estenosis anastomosis uretrovesical 6%.Hemos objetivado un porcentaje de márgenes positivos del 49,1%. No hemos tenido ningún exitusperoperatorio. La supervivencia global de la serie es del 98,5%, la supervivencia cáncer específica del 99,75%, y la supervivencia libre de enfermedad del 84,97%.Conclusiones: La prostatectomía radical es una excelente opción de tratamiento en pacientes con cáncer de próstata órgano confinado. Es indispensable para obtener buenos resultados una correcta selección de los pacientes candidatos a tratamiento quirúrgico (AU)

Objetive: To evaluate the complications and results of our series of 398 radical retropubic prostatectomies as an elective treatment for clinically localized prostate cancer. Patients and methods: Between january 1997 and june 2003, a total of 398 radical retropubic prostatectomies have been performed. Mean age was 63.8 years (45.8-78.2), mean PSA at diagnosis 9.32 ng/ml (0.9-129.7). Mean surgical time was 141.6 minutes (70-280), and mean hospitalization was 6.75 days (2-37). Results: Mean follow-up was 65.18 months. We report as peroperatory complications: rectal injury 1.8%, lymphatic leakage 0.3%, urinary fistula 5%. As delay complications: uretrovesical junction stenosis 6%. We observed 49.1% of patients with positive surgical margins. We don´t report any peroperatory death. The overall survival rate is 98.5%, the cancer specific survival rate is 99.75%, and the recurrence-free survival rate is 84.97%. Conclusions: Radical retropubic prostatectomy is an excellent treatment form for patients with clinically localized prostate cancer. A strict selection of patients candidates is important to obtain good results (AU)

[Retrospective study of 130 patients with organconfined prostate cancer treated with brachytherapy]. / Estudio retrospectivo de 130 pacientes con cáncer prostático organoconfinado tratados con braquiterapia prostática.

INTRODUCTION: The prostate brachytherapy with I 125 seeds has an indication in patients with organconfined prostate cancer. Our objective is to describe the population treated in our institution with permanent I125 seeds implants, the dosimetric characteristics of the technique and the preliminary results of our group-study in terms of evolution and toxicity. MATERIAL AND METHODS: Between May 2000 and March 2003, 130 patients with permanent implants of I125 seeds were treated. Beforehand we did prostate volumetric with transrectum prostate echography in order to assess the configuration of the implant, number of seeds and their place in the prostate with the objective to get a fine coverage of PTV (planet target volume). Stage distribution: 75.72% T1c; 24.28% T2a; Gleason<6, 94%. The PSA pretreatment average was 6.38 ng/ml. The average prostate volume was 30 cc. The 16.67% of the patients included had hormonal treatment previously to get the implants. The average age was 64 years. The characteristic techniques of the implants were: the average width of the needle as 24 (14-35) and the average of the seeds 76 (46-111). Finally the average activity was 0.39 mCi/seed, which means average total implant activity of 80 mCi. RESULTS: We analyzed 130 patients with average follow up 6 months. A 1 to 2 year surveillance was carried out on 98.9% and the global free disease surveillance (biochemic relapse) of 98.9% at the year and of the 87.8% at the end of the 2 years. The relapse in the low risk patients was 98.8% after the first year and 88.7% at the end of 2 year. On the contrary in the middle risk was of 100% and 83% respectively, although the amount of patients in significantly less. As a relevant acute secondary effects we found slight rectitys or GI (RTOG scale) in 1.4 and that needs synthomatic medication or GII (RTOG scale) in 0.8%. We found slide hematuria or GI (RTOG scale) in the 53% and other measures or GII (RTOG scale) in the 2.64% was needed. Finally we had to set a urinary prove for acute retention in 4.3%. CONCLUSION: The prostate brachyterapy is a complex procedure that needs a multidisciplinary team participation in order to be able to carry out. It avoids a long term hospitalization and allows for the patient to have daily activity within a short period of time. Despite the fact of the brief follow-up, the results over biochemical relapse and toxicity were similar to the ones in the literature. Tolerance to the implant was good. It would necessary a longer follow-up in order to be able to come to long term conclusions.

Estudio retrospectivo de 130 pacientes con cáncer prostático organoconfinado tratados con braquiterapia prostática / Retrospective study of 130 patients with organconfined prostate cancer trated with brachitherapy

Introducción: La braquiterapia prostática con semillas de I125 está indicada en pacientes con cáncer de próstata organoconfinado. Nuestro objetivo es describir la población tratada en nuestra institución mediante implante permanente con semillas de I125, las características dosimétricas de la técnica y los resultados preliminares de nuestra serie en cuanto a evolución y toxicidad. Material y métodos: Entre mayo 2000 y marzo de 2003 fueron tratados 130 pacientes con implante permanente transperineal de semillas de I125. Previamente a todos se les realizó volumetría mediante una ecografía prostática transrectal para determinar la configuración del implante, número de semillas y su localización en la próstata con el fin de obtener una adecuada cobertura del PTV (planed target volume o volumen planificado para tratar). Distribución por estadios: 75,72% T1c; 24,28% T2a. Gleason < 6, 94,24%. La mediana del PSA pretratamiento 6,38 ng/ml. El volumen prostático mediano fue de 30 cc. El 16,67% de los pacientes cuando los recibimos llevaban tratamiento hormonal previo al implante. La edad mediana fue de 64 años. En cuanto a las características técnicas de los implantes: la mediana de agujas utilizadas fue de 24 (14-35), y la mediana de semillas: 76 (46-111). Finalmente la mediana de la actividad fue de 0,39mCi/semilla, lo que supuso una actividad total implantada media de 80 mCi. Resultados: Analizamos los 130 pacientes con un seguimiento mínimo de 6 meses. La supervivencia a 1 y 2 años fue del 99,1% y la supervivencia libre de enfermedad global del 98,9% al año y del 87,8% a los dos años La supervivencia libre de enfermedad bioquímica en los pacientes de bajo riesgo eran, al año de 98,8% y a los dos años del 88,7%. Por el contrario en los de riesgo intermedio eran del 100% y del 83,3% respectivamente, aunque el número de pacientes es significativamente menor. Como efectos secundarios agudos relevantes encontramos rectitis leve o GI (escala de la RTOG) en 1,4% y que necesitó medicación sintomática o GII (escala de la RTOG) en 0,8%. Se presentó hematuria leve o GI (escala de la RTOG) el 53%, y que precisaran otras medidas o GII (escala de la RTOG) en el 2,64%. Finalmente hubo que colocar sonda urinaria por retención aguda el 4,3%. Conclusión: La braquiterapia prostática es un procedimiento complejo que exige la participación de un equipo multidisciplinar en su realización. Evita una hospitalización prolongada y permite al paciente recuperar sus actividades cotidianas en un periodo corto de tiempo. Aunque la media de seguimiento es corta, los resultados en cuanto a supervivencia libre de recidiva bioquímica y toxicidad son comparables a los descritos en la literatura. La tolerancia al implante ha sido buena. Es necesario un mayor seguimiento para poder establecer conclusiones a largo plazo

Introduction: The prostate brachitherapy with I 125 seeds has an indication in patients with organconfined prostate cancer. Our objective is to describe the population trated in our institution with permanent I125 seeds implants, the dosimetric characteristics of the technique and the preliminary results of our group-study in terms of evolution and toxicity. Material and methods: Between May 2000 and March 2003, a 130 patients with permanent implants of I125 seeds were trated. Beforehand we did prostate volumetric with transrectum prostate ecography in order to asses the configuration of the implant, number of seeds and their place in the prostate with the objective to get a fine coverage of PTV (planet target volume). Stage distribution: 75.72% T1c; 24.28% T2a. Gleason<6, 94%. The PSA pretreatment average was 6.38 ng/ml. The average prostate volume was 30 cc. The 16.67% of the patients included had hormonal treatment previously to get the implants. The average age was 64 years. The characteristic techniques of the implants were: the average width of the needle as 24 (14-35) and the average of the seeds 76 (46-111). Finally the average activity was 0.39 mCi/seed, wic means average total implant activity of 80 mCi. Results: We analized 130 patients with average follow up 6 months. A 1 to 2 year surveillance was carried out on 98.9% and the global free disease surveillance (biochemic relapse) of 98.9% at the year and of the 87.8% at the end of the 2 years. The relapse in the low risk patients was, 98.8% after the first year and 88.7% at the end of 2 year. On the contrary in the middle risk was of 100% and 83% respectively, although the amount of patients in significantly less. As a relevant acute secondary effects we found slight rectitys or GI (RTOG scale) in 1.4 and that needs synthomatic medication or GII (RTOG scale) in 0.8%. We found slide hematuria or GI (RTOG scale) in the 53% and other measures or GII (RTOG scale) in the 2.64% was needed. Finally we had to set a urinary prove for acute retention in 4.3%. Conclusion: The prostate brachiterapy is a complex procedure that needs a multidisciplinary team participation in order to be able to carry out. It aboids a long term hospitalitzation and allows for the patient to have daily activity within a short period of time. Despite the fact of the brief follow-up, the results over biochemical relaps and toxicity were similars to the ones in the literature. Tolerance to the implant was good. It would necessary a longer follow-up in order to be able to come to long term conclusions

Investigation of polymorphism in the MDR1 gene and antidepressant-induced mania.

The involvement of the multi-drug-resistant 1 P-glycoprotein gene (MDR1 P-gp) in the transport of antidepressants across the blood-brain barrier makes it a good candidate for the prediction of antidepressant response and side effects. We investigated the role of the MDR1 P-gp gene in predicting the induction of mania in bipolar patients (BP) treated with proserotonergic drugs. Participants met the DSM-IV criteria for BP or BPII and had at least one depressive episode treated with proserotonergic antidepressants. The first group (n=26) included patients with at least one DSM-IV manic/hypomanic episode developed during antidepressant treatment; the second group (N=29) included patients with no antidepressant-induced switches. The common polymorphism of the MDR1 was genotyped for both groups and comparison was made with respect to the presence/absence of induced mania between the two groups. No association between antidepressant-induced mania and the MDR1 alleles or genotypes was found (chi2=1.85, 2 df, P=0.39; chi2=0.13, 1 df, P=0.72).

Evidence that the N-methyl-D-aspartate subunit 1 receptor gene (GRIN1) confers susceptibility to bipolar disorder.

There is evidence for the involvement of glutamatergic transmission in the pathogenesis of major psychoses. The two most commonly used mood stabilizers (ie lithium and valproate) have been found to act via the N-methyl-D-aspartate receptor (NMDAR), suggesting a specific role of NMDAR in the pathogenesis of bipolar disorder (BP). The key subunit of the NMDAR, named NMDA-1 receptor, is coded by a gene located on chromosome 9q34.3 (GRIN1). We tested for the presence of linkage disequilibrium between the GRIN1 (1001-G/C, 1970-A/G, and 6608-G/C polymorphisms) and BP. A total of 288 DSM-IV Bipolar I, Bipolar II, or schizoaffective disorder, manic type, probands with their living parents were studied. In all, 73 triads had heterozygous parents for the 1001-G/C polymorphism, 174 for the 1970-A/G, and 48 for the 6608-G/C. These triads were suitable for the final analyses, that is, the transmission disequilibrium test (TDT) and the haplotype-TDT. For the 1001-G/C and the 6608-G/C polymorphisms, we found a preferential transmission of the G allele to the affected individuals (chi(2)=4.765, df=1, P=0.030 and chi(2)= 8.395, df=1, P=0.004, respectively). The 1001G-1970A-6608A and the 1001G-1970A-6608G haplotypes showed the strongest association with BP (global chi(2)=14.12, df=4, P=0.007). If these results are replicated there could be important implications for the involvement of the GRIN1 in the pathogenesis of BP. The role of the gene variants in predicting the response to mood stabilizers in BP should also be investigated.

Clinical variables related to suicide attempts in schizophrenic patients: a retrospective study.

In this study, we investigated the possible association between clinical or pharmacological variables and suicidal behavior in a sample of chronic schizophrenia or schizoaffective disorder patients. One hundred and three patients with a DSM-III-R diagnosis of chronic schizophrenia or schizoaffective disorder were studied. The sample was subdivided in two subsamples according to the presence/absence of suicidal attempts lifetime. The main demographic and clinical variables retrospectively collected were analyzed and compared between the two groups. Attempters had a significantly higher rate of nicotine abuse or dependence (chi-square=3.900, df=1, p<0.05, Odds Ratio (O.R.)=3.4), were more likely to have or have had lifetime major depressive episodes (chi-square=10.258, df=1, p<0.002, O.R.=6.5), were more likely to have a duration of untreated psychosis (DUP) > or =1 year (chi-square=6.228, df=1, p<0.02, O.R.=12.5), and were more frequently prescribed typical antipsychotics (chi-square=3.979, df=1, p<0.05, O.R.=6.5) than patients without suicidal attempts lifetime. Further investigations on larger samples and with prospective designs are warranted, particularly with respect to the role of early intervention and atypical antipsychotic treatment in reducing suicide risk in schizophrenic patients.

Reelin gene alleles and susceptibility to autism spectrum disorders.

A polymorphic trinucleotide repeat (CGG/GCC) within the human Reelin gene (RELN) was examined as a candidate gene for autism spectrum disorders (ASDs). This gene encodes a large extracellular matrix protein that orchestrates neuronal positioning during corticogenesis. The CGG-repeat within the 5' untranslated region of RELN exon 1 was examined in 126 multiple-incidence families. The number of CGG repeats varied from three to 16 in affected individuals and controls, with no expansion or contraction observed during maternal (n = 291) or paternal (n = 287) transmissions in families with autistic probands. Although the frequencies of the RELN alleles and genotypes in affected children were not different from those in the comparison group, a family-based association test (FBAT) showed that the larger RELN alleles (> or = 11 repeats) were transmitted more often than expected to affected children (S = 43, E(S) = 34.5, P = 0.035); this was particularly the case for the 13-repeat RELN allele (S = 22, E(S) = 16, P = 0.034). Affected sib-pair (ASP) analysis found no evidence of excess sharing of RELN alleles in affected siblings. The impact of genotypes with large alleles (> or = 11 repeats) on the phenotypes in individuals with ASD was analyzed by ANOVA in a subset of the families for which results of the Autism Diagnostic Interview-Revised were available. Children with large RELN alleles did not show any difference in scores for questions related to the core symptoms of autistic disorder, but there was a tendency for children with at least one large RELN allele to have an earlier age at first phrase (chi(2) = 3.538, P = 0.06). Thus, although the case-control and affected sib-pair findings did not support a role for RELN in susceptibility to ASD, the more powerful family-based association study demonstrated that RELN alleles with larger numbers of CGG repeats may play a role in the etiology of some cases of ASD, especially in children without delayed phrase speech.

Dopamine D4 receptor and tyrosine hydroxylase genes in bipolar disorder: evidence for a role of DRD4.

The involvement of the mesocorticolimbic dopamine system in behaviors that are compromised in patients with mood disorder has led to the investigation of dopamine system genes as candidates for bipolar disorder. In particular, the functional VNTRs in the exon III of the dopamine D4 (DRD4) and in intron I of the tyrosine hydroxylase (TH) genes have been investigated in numerous association studies that have produced contrasting results. Likewise, linkage studies in multiplex bipolar families have shown both positive and negative results for markers in close proximity to DRD4 and TH on 11p15.5. We performed a linkage disequilibrium analysis of the DRD4 and TH VNTRs in a sample of 145 nuclear families comprised of DSM-IV bipolar probands and their biological parents. An excess of transmissions and non transmissions was observed for the DRD4 4- and 2-repeat alleles respectively. The biased transmission showed a parent of origin effect (POE) since it was derived almost exclusively from the maternal meiosis (4-repeat allele maternally transmitted 40 times vs 20 times non-transmitted; chi(2) = 6.667; df = 1; P = 0.009; while paternally transmitted 26 times vs 21 times non-transmitted; chi(2) = 0.531; df = 1; P = 0.46). The analysis of TH did not reveal biased transmission of intron I VNTR alleles. Although replication of our study is necessary, the fact that DRD4 exhibit POE and is located on 11p15.5, in close proximity to a cluster of imprinted genes, suggests that genomic imprinting may be operating in bipolar disorder.

5HT1Dbeta Receptor gene implicated in the pathogenesis of Obsessive-Compulsive Disorder: further evidence from a family-based association study.

Obsessive-Compulsive Disorder (OCD) is a psychiatric condition with strong evidence for a genetic component and for the involvement of genes of the serotonin system. In a recent family-based association study we reported an association between the G allele of the G861C polymorphism of the 5HT1Dbeta receptor gene and OCD. The aim of the present study was to further investigate for the presence of linkage disequilibrium between each of two polymorphisms of the 5HT1Dbeta receptor gene and OCD in a larger sample of OCD families. In a total of 121 families the G861C and the T371G polymorphisms of the 5HT1Dbeta receptor gene were genotyped using standard protocols. The genotyping data were analyzed with a new extension of the Transmission Disequilibrium Test (FBAT). The phenotypes considered in the analyses were the diagnosis of OCD and two quantitative phenotypes related to the diagnosis and clinically relevant, ie, the age at onset and the severity of OCD symptoms. We confirmed the previously found preferential transmission of the G861 allele to the affected subjects (z = 2.262, P = 0.02). No significant association was found between the polymorphism and the quantitative phenotypes considered. These results represent a confirmation of our previous published study and thus, could have important implications for the role of the 5HT1Dbeta receptor gene in the pathogenesis and treatment of OCD. Further genetic investigations on this marker considering additional polymorphisms and other quantitative phenotypes related to OCD are warranted.

Simultaneous determination of clomipramine and its desmethyl and hydroxy metabolites in plasma of patients by high-performance liquid chromatography after solid-phase extraction.

Clomipramine (CMI) is a typical tricyclic antidepressant with a wide clinical spectrum, being used in major depressive, panic and obsessive-compulsive disorders. The relationship between clinical response and plasma levels of clomipramine and its N-desmethylated (N-desmethylclomipramine, DMCMI) and hydroxy-metabolites remains unclear. In particular, limited information is available on the correlation with clinical response in patients with obsessive-compulsive disorder (OCD). This study describes a new sensitive method to simultaneously determine CMI and its major N-desmethylated and hydroxy-metabolites present in human plasma by HPLC with a UV detector. After a solid-phase extraction from plasma (Isolute C2 columns) the separation of the compounds was performed on a Lichrospher CN column (250 x 4 mm, 5 microm with a 2-cm pre-column) by an eluent consisting of 10 mM K(2)HPO(4)-acetonitrile-methanol (35:25:40 v/v/v) at a flow of 1.5 ml/min. UV detector was set at 214 nm. The lower limit of quantification for all the analytes was at least 5 ng/ml. The coefficients of variation ranged between 2.0 and 4.9% with recovery rates between 97.0 and 100.3%. Linear regression analyses showed correlation coefficients between 0.98 and 0.99. This method is simple, fast and reliable with good specificity and sensitivity. Solid phase extraction is efficient and rapid, allowing the extraction of several plasma samples on the same day and may therefore be usefully and realistically applied in the clinical context. We thus investigated the relevance of plasma levels of CMI and its metabolites as a predictor of clinical outcome in a group of 15 patients with OCD.

Is olanzapine better than haloperidol in resistant schizophrenia? A double-blind study in partial responders.

INTRODUCTION: To compare the efficacy and safety of olanzapine and haloperidol in partial-responder paranoid schizophrenic patients. METHOD: In this multi-centre, double-blind study, 28 patients with DSM-IV paranoid schizophrenia were randomized to receive 14 weeks treatment with either olanzapine or haloperidol at flexible doses. The pre- and post-treatment assessment included the Brief Psychiatric Rating Scale (BPRS), the Scale for the Assessment of Negative Symptoms (SANS), the CGI, the Simpson-Angus Rating Scale, and the Barnes Akathisia Rating Scale. RESULTS: The two treatment groups showed similar improvement on the BPRS positive symptoms subscale, while the improvement of BPRS negative symptoms subscale was significant only in the olanzapine group (ANOVA with repeated measures, group effect: F=5.89, P =0.023). Only the olanzapine-treated patients experienced a significant improvement of negative symptoms as rated by the SANS (ANOVA with repeated measures, group effect: F=6.81, P =0.016). No significant differences were found between the two groups on the Simpson and Angus Rating Scale scores, but a significant difference was found in the Barnes Akathisia Rating Scale scores: no patient in the olanzapine-treated group experienced akathisia, while a few patients in the haloperidol-treated group showed this side-effect, thus resulting in a significant group effect detected by the ANOVA (F=4.23, P =0.05). CONCLUSIONS: These preliminary results suggest that olanzapine is superior to haloperidol in the treatment of partial-responder paranoid schizophrenic patients, and also shows a better tolerability profile. Further investigations, including different diagnostic subgroups, are still needed to further clarify the clinical profile of olanzapine. (Int J Psych Clin Pract 2002; 6: 107-111).