Collaborative meta-analysis finds no evidence of a strong interaction between stress and 5-HTTLPR genotype contributing to the development of depression.

The hypothesis that the S allele of the 5-HTTLPR serotonin transporter promoter region is associated with increased risk of depression, but only in individuals exposed to stressful situations, has generated much interest, research and controversy since first proposed in 2003. Multiple meta-analyses combining results from heterogeneous analyses have not settled the issue. To determine the magnitude of the interaction and the conditions under which it might be observed, we performed new analyses on 31 data sets containing 38 802 European ancestry subjects genotyped for 5-HTTLPR and assessed for depression and childhood maltreatment or other stressful life events, and meta-analysed the results. Analyses targeted two stressors (narrow, broad) and two depression outcomes (current, lifetime). All groups that published on this topic prior to the initiation of our study and met the assessment and sample size criteria were invited to participate. Additional groups, identified by consortium members or self-identified in response to our protocol (published prior to the start of analysis) with qualifying unpublished data, were also invited to participate. A uniform data analysis script implementing the protocol was executed by each of the consortium members. Our findings do not support the interaction hypothesis. We found no subgroups or variable definitions for which an interaction between stress and 5-HTTLPR genotype was statistically significant. In contrast, our findings for the main effects of life stressors (strong risk factor) and 5-HTTLPR genotype (no impact on risk) are strikingly consistent across our contributing studies, the original study reporting the interaction and subsequent meta-analyses. Our conclusion is that if an interaction exists in which the S allele of 5-HTTLPR increases risk of depression only in stressed individuals, then it is not broadly generalisable, but must be of modest effect size and only observable in limited situations.

The genetics of bipolar disorder: genome 'hot regions,' genes, new potential candidates and future directions.

Bipolar disorder (BP) is a complex disorder caused by a number of liability genes interacting with the environment. In recent years, a large number of linkage and association studies have been conducted producing an extremely large number of findings often not replicated or partially replicated. Further, results from linkage and association studies are not always easily comparable. Unfortunately, at present a comprehensive coverage of available evidence is still lacking. In the present paper, we summarized results obtained from both linkage and association studies in BP. Further, we indicated new potential interesting genes, located in genome 'hot regions' for BP and being expressed in the brain. We reviewed published studies on the subject till December 2007. We precisely localized regions where positive linkage has been found, by the NCBI Map viewer (http://www.ncbi.nlm.nih.gov/mapview/); further, we identified genes located in interesting areas and expressed in the brain, by the Entrez gene, Unigene databases (http://www.ncbi.nlm.nih.gov/entrez/) and Human Protein Reference Database (http://www.hprd.org); these genes could be of interest in future investigations. The review of association studies gave interesting results, as a number of genes seem to be definitively involved in BP, such as SLC6A4, TPH2, DRD4, SLC6A3, DAOA, DTNBP1, NRG1, DISC1 and BDNF. A number of promising genes, which received independent confirmations, and genes that have to be further investigated in BP, have been also systematically listed. In conclusion, the combination of linkage and association approaches provided a number of liability genes. Nevertheless, other approaches are required to disentangle conflicting findings, such as gene interaction analyses, interaction with psychosocial and environmental factors and, finally, endophenotype investigations.

The role of specific early trauma in adult depression: A meta-analysis of published literature. Childhood trauma and adult depression.

BACKGROUND: A large literature has long focused on the role of trauma in childhood and risk for psychological disorders in adulthood. Despite several studies performed, to date, it is not clear which weight have different childhood stressors specifically on the risk for depression in adult life. In the present study, we performed a meta-analysis of the literature in order to assess the effective role of childhood traumas as risk factor in the onset of depressive disorders in adults. METHODS: Previously published papers investigating the exposure to childhood trauma and their association with depression in adult subjects were retrieved in literature through common databases. Meta-analysis was conducted by the RevMan software. The quality of studies was evaluated by an adapted version of the New-Ottawa Quality Assessment Scale; bias publication was evaluated by the Egger's test. Meta-regression analysis was employed to detect potential confounders and/or moderating variables. Finally, a sensitivity analysis was post-hoc performed to control for potential confounders. RESULTS: Emotional abuse showed the strongest association with depression (OR=2.78) followed by neglect (OR=2.75) and sexual abuse (OR=2.42). Significant associations were also found for domestic violence (OR=2.06) and physical abuse (OR=1.98). Nevertheless, in post-hoc analysis, emotional abuse and neglect showed the strongest associations with depression as compared to other kinds of child trauma. CONCLUSIONS: These findings support the role of neglect and emotional abuse as significantly associated to depression. Sexual/physical abuse or violence in family may be unspecific risk factors for mental disturbance. Other kind of trauma may play a less relevant role in risk of adult depression, though they should be not underestimated.

Influence of 5-HTTLPR and TPH variants on illness time course in mood disorders.

The aim of our study was to investigate gene variants in the long-term outcome of mood disorders. We retrospectively studied a sample of inpatients affected by recurrent and rapid cycling mood disorders. The serotonin transporter gene-linked functional polymorphic region (5-HTTLPR) and the A218C tryptophan hydroxylase (TPH) gene variant were determined using a PCR-based technique. For 5-HTTLPR polymorphism we genotyped 435 inpatients affected by major depressive (n=153), bipolar (n=213) and rapid cycling (n=69) mood disorders and 456 controls; for TPH we genotyped 399 inpatients (MD, n=132; BP, n=203; rapid cycling n=64) and 259 controls. Random Regression Model analysis was used to investigate the longitudinal time course of the illness. 5-HTTLPR and TPH polymorphisms were not associated with mood disorders time course. However we observed an excess of 5-HTTLPR*long alleles among rapid cycling subjects compared to both controls (P=0.018) and remitting mood disorders (P=0.006). TPH frequencies did not differ between mood disorders subtypes. Our results suggest that 5-HTTLPR variants may confer a susceptibility toward rapid cycling mood disorders.

Impact of clinical variables on illness time course in mood disorders.

The aim of this study is to investigate possible clinical predictors of the long-term outcome of mood disorders. We undertook a retrospective assessment of 426 inpatients affected by major depressive disorder (n=182) and bipolar disorder (n=244), with at least two episodes of illness alternating with complete recovery; subjects were affected for an average of 14.43+/-11.34 years and presented an average of 4.4+/-2.1 episodes. Random regression model analysis (http://www.uic.eu/hedeker/mix.html) was used to investigate the longitudinal time course of the illness. A progressive cycle shortening was observed, whereby the more episodes a subject experienced, the shorter the interval was between episodes, up to a plateau frequency of one episode/year on average. Bipolar diagnosis was the strongest predictive factor toward high frequency of episodes; a manic onset among bipolars was associated with an even worse outcome. Gender, education level, family history, duration of the first interval, severity of the first episode, lifetime mean severity and lifetime mean treatment level were not associated with outcome in terms of episode frequency. Our results suggest that recurrent affective disorders recruited in a clinical setting have a marked deteriorating mean time course.

[Our experience in carcinoma of the stomach (clinico-statistical contribution)]. / Nostra esperienza sul carcinoma dello stomaco (contributo clinico statistico).

The study population consisted of 168 patients suffering from gastric cancer. The authors conclude that the only way of achieving a satisfactory improvement in the long-term prognosis of this disease is by early diagnosis, greater involvement of general practitioners and rapid referral of patients to a digestive endoscopy unit.

[Long-term evaluation of the treatment of peptic ulcer by the Billroth II method]. / Valutazioni a distanza sul trattamento dell'ulcera peptica mediante resezione secondo Billroth II.

120 patients subjected to Billroth II gastrectomy over the period 1966-1982 were evaluated. The very satisfactory results obtained in our experience persuade us that this technique is still extremely valid.

[Bilio-digestive anastomosis (our experience)]. / Le anastomosi bilio-digestive (nostra esperienza).

The authors have conducted a retrospective study of surgical therapy by bilio-digestive anastomosis of benign and malignant diseases of the common bile duct. They conclude that this procedure should only be used when the anatomical and clinical conditions do not allow other surgical techniques to be employed.

[Intestinal localizations of non-Hodgkin's lymphoma (clinical and histopathologic considerations)]. / Localizzazioni intestinali del linfoma N.H. (considerazioni cliniche e istopatologiche).

The authors describe two cases of malignant lymphoma localized in the rectum and caecum respectively and, taking into account the data reported in the literature, comment on current classifications and on the latest typing methods, particularly those based on radio-immunological assay. They stress the importance of a uniform clinical classification for diagnostic and therapeutic purposes as well as the increasing amount of interest in these neoplasms, especially in relation to those carcinomas where differential diagnosis does not always prove an easy matter.

[Fournier syndrome (description of 2 clinical cases)]. / Sindrome di Fournier (descrizione di due casi clinici).

The Authors describe two cases of Fournier's syndrome, a rare disease consisting in gangrene of the scrotum, penis skin and perineum, stressing the importance of construction of an intestinal diversion for healing this unusual condition.

[The use of the Kehr tube in choledochal calculi (our experience)]. / Impiego del tubo di Kehr nella calcolosi del coledoco (nostra esperienza).

Surgical therapy of the main bile duct is an important aspect of liver disease. The authors examine the advisability of using a Kehr drain in benign and malignant disease of the main bile duct, and draw the conclusion that, with precise indications, this technique still has an important role to play in the resolution of biliary tract disease.

[Intestinal occlusion due to metastases of malignant melanoma (a clinical case)]. / Occlusione intestinale da metastasi di melanoma maligno (caso clinico).

Metastases of the gastrointestinal tract from malignant melanoma are fairly frequent, though their detection during the patient's lifetime is rare. An antemortem diagnosis, however, may not necessarily be an indication for surgery, unless in the presence of an acute complication (intestinal occlusion, perforation, or severe haemorrhage), owing to the patient's degenerated general condition, the presence of secondaries in other sites and, above all, the rare occurrence of major gastrointestinal disorders. The authors describe their experience with a patient presenting acute intestinal occlusion and operated on three years previously for malignant melanoma of the scalp.

[Biliary ileus (description of 2 clinical cases)]. / L'ileo biliare (descrizione di due casi clinici).

Biliary ileus is a rare complication of the biliary pathology, appearing through obstructive pictures of patients in advanced age. After a careful study about this subject, the authors report two cases they had he opportunity to observe.

[Follow-up clinical evaluation of raffia treatment of perforated peptic ulcer]. / Valutazioni cliniche a distanza sul trattamento con rafia dell'ulcera peptica perforata.

The authors, analysing their casuistry of 56 cases of perforated peptic ulcer, treated with simple raffia, think this surgical act, although simple, has its own therapeutical meaning in conditions of emergency such as a peritonitic abdomen. A remote checking of such patients demonstrates the validity of said therapeutical behaviour.

[Diverticulosis and diverticular disease (reference to a case of diverticular disease observed in 3 sisters)]. / Diverticolosi e malattia diverticolare (riferimento a un caso di malattia diverticolare osservato in 3 sorelle).

We started from this frequent and important intestinal pathology to emphasize the above mentioned observation of three cases where it was possible to apply three different medico-surgical techniques with excellent results.

Serotonin transporter gene variants and prediction of stress-induced risk for psychological distress.

The response to psychosocial stress is influenced by both psychosocial factors and genetic vulnerability. The most investigated gene in gene × environment studies in abnormal response to environmental stressors is the one coding for the serotonin transporter (SLC6A4). Variability within this gene has been associated with functional brain differences, personality dimensions, reactivity to stress and risk for various psychopathological conditions. In the present study, we set out to investigate the association of common genetic variants within SLC6A4 with state psychopathology in a community sample homogeneously exposed to stress, thus inquiring about potential genetic differences in stress sensitivity. One thousand eight hundred seventy-five young conscripts were evaluated for psychopathological distress with the 90-item Symptoms Checklist Revised in their first 2 weeks of admission to obligatory military service. Of these, 1594 were genotyped for the biallelic ins/del polymorphism (5-HTTLPR S/L) within the promoter region of SLC6A4, as well as the variation within the 'long' 5-HTTLPR allele (rs25531A/G). Homozygous for the 5-HTTLPR S allele reported significantly higher scores for paranoid ideation as compared with L-allele carriers. Slight effects on other subscales were observed, but were not significant after correction for multiple testing. Despite limitations linked to the evaluation of psychopathology by a single general scale and multiple comparisons, the present study support a role of SLC6A4 in modulating abnormal responses to environmental stress. In particular, variation within this gene may confer risk for paranoid/defensive reactions under conditions of environmental stress associated with military induction.

A protective genetic variant for adverse environments? The role of childhood traumas and serotonin transporter gene on resilience and depressive severity in a high-risk population.

Genetic aspects may influence the effect of early adverse events on psychological well being in adulthood. In particular, a common polymorphism within the serotonin transporter gene (5-HTTLPR short/long) has been associated to the risk for stress-induced psychopathology. In the present study we investigated the role of childhood traumas and 5-HTTLPR on measures of psychological resilience and depression in a sample of individuals at a high risk for psychological distress (763 male prisoners). The 5-HTTLPR genotype did not influence resilience and depressive severity. However, a significant interaction was observed between 5-HTTLPR and childhood traumas on both resilience and depressive severity. In particular, among subjects exposed to severe childhood trauma only, the long-allele was associated to lower resilience scores and increased current depressive severity as compared to short/short homozygous. Sex specific effects, difference in type and duration of stressors and the specific composition of the sample may explain discrepancy with many studies reporting the short-allele as a vulnerability factor for reactivity to stress. We here speculated that in males the long-allele may confer lower resilience and therefore higher vulnerability for depressive symptoms in subjects exposed to early stress and currently living in stressful environments.

Serotonin transporter gene associated with lithium prophylaxis in mood disorders.

The aim of this study was to investigate the possible association between the functional polymorphism in the upstream regulatory region of the serotonin transporter gene (5-HTTLPR) and the prophylactic efficacy of lithium in mood disorders. Two hundred and one subjects affected by bipolar (n = 167) and major depressive (n = 34) disorder were followed prospectively for an average of 58.2 months and were typed for their 5-HTTLPR variant using polymerase chain reaction techniques. 5-HTTLPR variants were associated with lithium outcome (F = 5.35; df = 2,198; P = 0.005). Subjects with the s/s variant showed a worse response compared to both l/s and l/l variants. Consideration of possible stratification effects such as sex, polarity, age at onset, duration of lithium treatment and previous episodes did not influence the observed association. 5-HTTLPR variants may be a possible influencing factor for the prophylactic efficacy of lithium in mood disorders.

Further evidence for a possible association between serotonin transporter gene and lithium prophylaxis in mood disorders.

We previously reported an association between the functional polymorphism in the upstream regulatory region of the serotonin transporter gene (SERTPR) and the prophylactic efficacy of lithium in a sample of 201 Italian subjects affected by Mood disorders. The aim of the present study was to replicate analyses on an independent sample. In total, 83 subjects affected by Bipolar disorder were recruited in the Mood Disorders Clinic of the Eginition Hospital of the Athens University, Medical School Department of Psychiatry. All patients were administered with lithium as prophylactic therapy and they were prospectively observed for at least 3 years. Subjects were typed for their SERTPR variant using polymerase chain reaction techniques. SERTPR variants were associated with lithium outcome among those subjects who had few manic episodes before lithium treatment and, as a trend, among subjects who received a high daily dose of lithium (> or =1200 mg/die). In both cases, subjects with the l/l variant showed a higher probability to develop an illness episode within 3 years of prophylactic treatment with lithium. The present study confirmed our previous observation of a better response of SERTPR*l/s carriers, but could not confirm a poor efficacy in subjects with the SERTPR*s/s genotype. Notwithstanding the conflicting results, SERTPR variants are a possible liability factor for lithium long-term efficacy in mood disorders. Further studies on independent and large samples are required to determine the reliability and direction of the possible association between SERTPR variants and lithium outcome.