Psychosis-inducing effects of cannabis are related to both childhood abuse and COMT genotypes.

OBJECTIVE: To test whether the association between childhood abuse, cannabis use and psychotic experiences (PEs) was moderated by the COMT (catechol-O-methyltransferase) gene. METHOD: Psychotic experiences (PEs), childhood abuse, cannabis use and COMT Val158Met genotypes were assessed in 533 individuals from the general population. Data were analysed hierarchically by means of multiple linear regression models. RESULTS: Childhood abuse showed a significant main effect on both positive (ß = 0.09; SE = 0.04; P = 0.047) and negative PEs (ß = 0.11; SE = 0.05; P = 0.038). A significant three-way interaction effect was found among childhood abuse, cannabis use and the COMT gene on positive PEs (ß = -0.30; SE = 0.11; P = 0.006). This result suggests that COMT genotypes and cannabis use only influenced PE scores among individuals exposed to childhood abuse. Furthermore, exposure to childhood abuse and cannabis use increased PE scores in Val carriers. However, in individuals exposed to childhood abuse but who did not use cannabis, PEs increased as a function of the Met allele copies of the COMT gene. CONCLUSION: Cannabis use after exposure to childhood abuse may have opposite effects on the risk of PEs, depending on the COMT genotypes providing evidence for a qualitative interaction. Val carriers exposed to childhood abuse are vulnerable to the psychosis-inducing effects of cannabis.

A 6-month prospective, observational, naturalistic, uncontrolled study to evaluate the effectiveness and tolerability of oral ziprasidone in patients with schizophrenia.

This multicenter, uncontrolled, naturalistic study evaluated the effectiveness and tolerability of 6 months of treatment with ziprasidone in 1266 patients with a diagnosis of schizophrenia. The percentage of responders (at least 30% reduction in PANSS total score) in the primary analysis sample (n=1022) was 47.3% (95% CI 44.2-50.4) at the end of the study. Patients showed a significant and clinically relevant reduction in the PANSS total, positive, negative and general psychopathology subscales scores (effect size of 1.60, 1.83, 0.62 and 1.40 respectively). Overall, 453 (35.8%) patients withdrew from the study; 9.3% withdrew owing to adverse events. Ziprasidone doses greater than 120 mg/day were associated with a lower risk of discontinuation for any cause (OR 0.46, 95% CI 0.33-0.65) Ziprasidone was well tolerated. Most common side effects were: insomnia, somnolence and nervousness. The effectiveness and tolerability of ziprasidone in clinical practice are consistent to those previously shown in the more restricted and homogeneous populations of clinical trials.

Impaired response inhibition in obsessive compulsive disorder.

OBJECTIVE: The present study investigates different three inhibitory control functions in patients with obsessive-compulsive disorder (OCD). Selective motor response inhibition was tested in a GO/NO-GO paradigm, the inhibition of a triggered motor response in a STOP paradigm and the ability to inhibit cognitive interference in a motor STROOP paradigm. METHODS: 27 patients who met DSM-IV criteria for OCD and 25 age, handedness and IQ-matched healthy control subjects were tested in the GO/NO-GO, STOP and motor STROOP tasks. RESULTS: OCD patients performed significantly worse than controls in the selective inhibition of their motor responses (GO/NO-GO) and in the inhibition of cognitive interference (STROOP), and also showed worse performance in suppressing previously triggered motor responses (STOP). CONCLUSION: Patients with OCD are impaired in motor and cognitive inhibitory mechanisms. The findings are consistent with psychobiological and neuropsychological models of OCD suggesting impairment of frontostriatal circuitries that mediate functions of inhibitory control.

Subtyping obsessive-compulsive disorder: clinical and immunological findings in child and adult onset.

It has been suggested that certain kinds of childhood OCD with specific clinical, biological and immunological characteristics may form a subgroup of OCD. We study the presence of these characteristics in child onset OCD and propose that the disorder be considered as a subtype of adult OCD. Forty adult patients with OCD were divided in two groups according to time of disease onset: 18 early onset and 21 late. Both sets were compared with a control group of 14 psychiatric patients. Child onset OCD was associated with higher mean ASLO titers, higher frequencies of history of tic disorders and tonsillitis in childhood and compulsive symptoms. No differences were found in D8/17 antibody titers or in other autoimmune parameters. The findings suggest that child onset OCD can be considered as a subgroup of adult OCD, although more specific biological markers are needed to identify it.

Endothelial damage in major depression patients is modulated by SSRI treatment, as demonstrated by circulating biomarkers and an in vitro cell model.

There is a link between depression, cardiovascular events and inflammation. We have explored this connection through endothelial dysfunction, using in vivo and in vitro approaches. We evaluated circulating biomarkers of endothelial dysfunction in patients with major depression at their diagnosis (MD-0) and during antidepressant treatment with the selective serotonin reuptake inhibitor escitalopram, for 8 and 24 weeks (MD-8 and MD-24). Results were always compared with matched healthy controls (CON). We measured in vivo circulating endothelial cells (CECs) and endothelial progenitor cells (EPCs) in blood samples, and assessed plasma levels of soluble von Willebrand factor (VWF) and vascular cell adhesion molecule-1 (VCAM-1). CEC counts, soluble VWF and VCAM-1 were statistically elevated in MD-0 (P<0.01 versus CON) and gradually decreased during treatment. Conversely, EPC levels were lower in MD-0, tending to increase throughout treatment. In vitro studies were performed in human endothelial cells cultured in the presence of sera from each study group. Elevated expression of the inflammation marker intercellular adhesion molecule-1 and oxidative stress, with lower presence of endothelial nitric oxide synthase and higher reactive oxygen species production, were found in cells exposed to MD-0 sera (P<0.05 versus CON). These results were normalized in cells exposed to MD-24 sera. Thrombogenicity of extracellular matrices generated by these cells, measured as expression of VWF, tissue factor and platelet reactivity, showed non-significant differences. We provide a model of cultured endothelial cells reproducing endothelial dysfunction in naive patients with major depression, demonstrating endothelial damage and inflammation at diagnosis, and recovering with selective serotonin reuptake inhibitor treatment for 24 weeks.

Patient-rated emotional and physical functioning among hematologic cancer patients during hospitalization for stem-cell transplantation.

In this 3-year prospective inpatient study, 220 patients received stem-cell transplantation (SCT) for hematologic cancer at a single institution. The objective of the study is to provide data on patient-rated emotional (depression and anxiety) and physical (overall physical status, energy level, and systemic symptomatology) functioning during hospitalization for SCT and to compare whether these differ between autologous and allogeneic SCT. Patients were assessed at hospital admission (T1), day of SCT (T2), and 7 days (T3) and 14 days (T4) after SCT, yielding a total of 852 evaluations. For the overall sample, anxiety was highest at T1 and decreased afterwards; a marked worsening in physical health status variables corresponded with a sharp increase in depression from T1 to T3, and was followed by an improvement in physical health and a reduction of depression. Compared to allogeneic SCT, a better physical outcome for autologous SCT was demonstrated by the significant group effect for systemic symptomatology and by the significant group x time interaction for overall physical status and energy level; there were no significant differences in depression or anxiety between SCT groups. These findings have implications for treatment decision making, coping with the transplantation process, and improving prevention and treatment strategies.

Polymorphic variation in the epigenetic gene DNMT3B modulates the environmental impact on cognitive ability: a twin study.

BACKGROUND: Though cognitive abilities in adulthood are largely influenced by individual genetic background, they have also been shown to be importantly influenced by environmental factors. Some of these influences are mediated by epigenetic mechanisms. Accordingly, polymorphic variants in the epigenetic gene DNMT3B have been linked to neurocognitive performance. Since monozygotic (MZ) twins may show larger or smaller intrapair phenotypic differences depending on whether their genetic background is more or less sensitive to environmental factors, a twin design was implemented to determine if particular polymorphisms in the DNMT3B gene may be linked to a better (worse) response to enriched (deprived) environmental factors. METHODS: Applying the variability gene methodology in a sample of 54 healthy MZ twin pairs (108 individuals) with no lifetime history of psychopathology, two DNMT3B polymorphisms were analyzed in relation to their intrapair differences for either intellectual quotient (IQ) or working memory performance. RESULTS: MZ twin pairs with the CC genotype for rs406193 SNP showed statistically significant larger intrapair differences in IQ than CT pairs. CONCLUSIONS: Results suggest that DNMT3B polymorphisms may explain variability in the IQ response to either enriched or impoverished environmental conditions. Accordingly, the applied methodology is shown as a potentially valuable tool for determining genetic markers of cognitive plasticity. Further research is needed to confirm this specific result and to expand on other putative genetic markers of environmental sensitivity.

Genome-wide methylation study on depression: differential methylation and variable methylation in monozygotic twins.

Depressive disorders have been shown to be highly influenced by environmental pathogenic factors, some of which are believed to exert stress on human brain functioning via epigenetic modifications. Previous genome-wide methylomic studies on depression have suggested that, along with differential DNA methylation, affected co-twins of monozygotic (MZ) pairs have increased DNA methylation variability, probably in line with theories of epigenetic stochasticity. Nevertheless, the potential biological roots of this variability remain largely unexplored. The current study aimed to evaluate whether DNA methylation differences within MZ twin pairs were related to differences in their psychopathological status. Data from the Illumina Infinium HumanMethylation450 Beadchip was used to evaluate peripheral blood DNA methylation of 34 twins (17 MZ pairs). Two analytical strategies were used to identify (a) differentially methylated probes (DMPs) and (b) variably methylated probes (VMPs). Most DMPs were located in genes previously related to neuropsychiatric phenotypes. Remarkably, one of these DMPs (cg01122889) was located in the WDR26 gene, the DNA sequence of which has been implicated in major depressive disorder from genome-wide association studies. Expression of WDR26 has also been proposed as a biomarker of depression in human blood. Complementarily, VMPs were located in genes such as CACNA1C, IGF2 and the p38 MAP kinase MAPK11, showing enrichment for biological processes such as glucocorticoid signaling. These results expand on previous research to indicate that both differential methylation and differential variability have a role in the etiology and clinical manifestation of depression, and provide clues on specific genomic loci of potential interest in the epigenetics of depression.

The 5-HT(2A) receptor gene 102T/C polymorphism is associated with suicidal behavior in depressed patients.

Several lines of evidence suggest that genetic factors constitute an important determinant of suicidal behavior. A significant association between the 5-HT(2A)-C allele and suicidality has recently been reported. The aim of this study was to investigate whether the proposed association between 5-HT(2A)-102T/C polymorphism and suicidality could be replicated in a larger and independent sample of Spanish patients with major depression. The 102T/C polymorphism of the 5-HT(2A) receptor gene was analyzed in 159 patients with major depression (DSM-IV criteria) and 164 unrelated and healthy controls using a case control design. All individuals were subjects of Spanish origin. Significant differences in allele (chi-square = 4.13, df = 1, P = 0.04) and genotype (chi-square = 6.19, df = 2, P = 0.04) distributions were found between non-suicide attempters and suicide attempters. Moreover, those patients carrying 5-HT(2A)-C allele had more than five times the risk for attempting suicide than noncarriers (OR = 5.50, 95% CI = 1.18-35.20, P = 0.01). Our results replicate the proposed association between 5HT(2A)-C allele and suicidality in major depression. Moreover, no overall associations are detected when patients with major depression and controls are compared for 102T/C frequencies, suggesting that the increased risk for suicidality conferred by 5-HT(2A)-C allele is primarily associated with suicidal behavior and not with the diagnosis of major depression itself.

Clinical factors associated with treatment noncompliance in euthymic bipolar patients.

BACKGROUND: Noncompliance with medication is a very common feature among bipolar patients. Rates of poor compliance may reach 64% for bipolar disorders, and noncompliance is the most frequent cause of recurrence. Knowledge of the clinical factors associated with noncompliance would enhance clinical management and the design of strategies to achieve a better outcome for bipolar patients. Although most patients withdraw from medication during maintenance treatment, compliance studies in euthymic bipolar samples are scarce. METHOD: Compliance treatment and its clinical correlates were assessed at the end of 2-year follow-up in 200 patients meeting Research Diagnostic Criteria for bipolar I or bipolar II disorder by means of compliance-focused interviews, measurements of plasma concentrations of mood stabilizers, and 2 structured interviews: the Schedule for Affective Disorders and Schizophrenia and the Structured Clinical Interview for DSM-III-R Axis II disorders. Well-compliant patients and poorly compliant patients were compared with respect to several clinical and treatment variables. RESULTS: The rate of mildly and poorly compliant patients was close to 40%. Comorbidity with personality disorders was strongly associated with poor compliance. Poorly compliant patients had a higher number of previous hospitalizations, but reported fewer previous episodes. The type of treatment was not associated with compliance. CONCLUSION: Clinical factors, especially comorbidity with personality disorders, are more relevant for treatment compliance than other issues such as the nature of pharmacologic treatment. Compliant patients may have a better outcome in terms of number of hospitalizations, but not necessarily with respect to the number of episodes. Bipolar patients, especially those with personality disorders, should be monitored for treatment compliance.

Efficacy and safety of risperidone in the treatment of schizoaffective disorder: initial results from a large, multicenter surveillance study. Group for the Study of Risperidone in Affective Disorders (GSRAD).

BACKGROUND: An adequate therapy for psychotic disorders needs to be effective against mood as well as psychotic symptoms. Analyses of data from clinical trials of risperidone in schizophrenia and small open-label studies in mania suggest that risperidone may have this broad efficacy profile. We present data on a 6-week trial of risperidone for the treatment of schizoaffective disorder that was part of a larger, 6-month surveillance study of patients with affective disorders. METHOD: One hundred two patients suffering from schizoaffective disorder (DSM-IV or ICD-10) entered the trial. Inclusion criteria consisted of a current DSM-IV diagnosis of schizoaffective disorder, bipolar type; DSM-IV manic or mixed psychotic episode; and a Young Mania Rating Scale (YMRS) score > 7 for a mixed episode (> 20 for a manic episode). Assessments included the YMRS, the Positive and Negative Syndrome Scale (PANSS), the Hamilton Rating Scale for Depression (HAM-D), the 4-item Clinical Global Impressions (CGI) scale, and the UKU Side Effect Rating Scale subscale for neurologic side effects. For patients entering the study, open-label risperidone therapy was added to their existing regimens of mood-stabilizing treatments. Other antipsychotic drugs were not allowed. RESULTS: Ninety-five patients completed the 6-week trial. At week 6, the mean +/- SD dose of risperidone was 4.7+/-2.5 mg/day. The mean scores on the assessment scales at baseline and week 6 (unless otherwise stated) were as follows: YMRS, 22.7 and 4.7, an improvement of 18.0 points (p < .0001); PANSS (at baseline and week 4), 74.1 and 54.2, an improvement of 19.9 points (p < .0001); HAM-D, 14.0 and 7.4, an improvement of 6.6 points (p < .0001); CGI (at baseline and week 4), 2.6 and 1.7, an improvement of 0.9 points (p < .0001). At week 4, most patients had shown improvement in symptom severity, and 9.3% were completely symptom-free. There were no statistically significant differences between baseline and week 4 in the severity of extrapyramidal symptoms as measured by the UKU. Risperidone was well tolerated; side effects were few and generally mild. CONCLUSION: The results to date with risperidone indicate that it may have both antipsychotic and mood-stabilizing properties. Despite the limitations of the open-label design, the results indicate that risperidone is a safe and effective therapy in combination with mood-stabilizers for the treatment of patients with manic, hypomanic, and depressive symptoms of mixed episodes in schizoaffective disorder, bipolar type.

Genetic variation in the 5-HT5A receptor gene in patients with bipolar disorder and major depression.

In the present study, genetic variation of the 5-HT5A receptor was analyzed in patients affected by affective disorders and healthy controls. The sample consisted of 181 patients with major depression, 88 patients with bipolar affective disorder (BP) and 157 unrelated controls (C), all of Spanish origin. Two polymorphisms (-19G/C and 12A/T) in the 5-HT5A receptor gene were analyzed by polymerase chain reaction amplification and subsequent enzyme digestion. No genotype, allele or haplotype differences were found when we compared patients and controls. When clinical variables were considered as possible tools for detecting genetic heterogeneity, no differences were found. Our results suggest that the polymorphisms analyzed in the 5-HT5A receptor gene do not play a major role in the pathogenesis of affective disorders.

Serious suicide attempts in affective patients.

A retrospective study was carried out including all patients who in the previous 6 years had required admission to our hospital for medical or surgical reasons following attempted suicide (n = 257). Those diagnosed as having affective disorder (n = 96), according to DSM-IIIR criteria, were compared with the other non-affective suicide attempters (n = 161). Affective patients were significantly different in that they were older, more often women, married or widowed, usually used non-violent methods, made more serious attempts and presented a higher incidence of concomitant physical illness. Affective patients with a history of previous attempts were more likely to be recurrent unipolar depressives or first episode unipolars with a concurrent diagnosis of personality disorder. Most of the depressed patients made the attempt within the first 12 months of the episode. Patients who attempted suicide in the first 12 months of the depression were more likely to use non-violent methods and to receive a diagnosis of bipolar or unipolar recurrent disorder.

Predictors of antidepressant treatment outcome in melancholia: psychosocial, clinical and biological indicators.

Predictive variables of response to imipramine and to phenelzine at 6 weeks and 6 months were studied in 116 patients suffering from major depression with melancholia (DSM-III). Several sociodemographic, clinical, and biological variables were studied. For imipramine-treated patients, high social support predicted a better response at 6 weeks, while development of hypomania during follow-up was associated with a better response at 6 weeks; absence of life events during the 6-month follow-up and initial non-suppression of dexamethasone predicted a better outcome at 6 months. For phenelzine-treated patients, development of hypomania during follow-up was associated with a better outcome at 6 months and absence of life events prior to the onset of the episode was associated with a worse outcome at 6 months.

Role of risperidone in bipolar II: an open 6-month study.

BACKGROUND: Since treatment approaches thought to be useful for mania are presumably suitable for hypomania as well, little systematic research has been done on the treatment of hypomanic episodes and their long-term outcome. As systematic trials have shown that the atypical antipsychotic risperidone may be effective and safe in the treatment of acute mania, we decided to conduct an open-label study of its effectiveness and tolerability in hypomania associated with bipolar II. METHODS: Forty-four DSM-IV bipolar II patients with Young Mania Rating Scale (YMRS) scores above 7 were included and followed-up for 6 months. Efficacy was measured by means of the YMRS and the Clinical Global Impression for Bipolar Disorder (CGI-BD). Treatment-emergent depression was measured by the Hamilton Depression Rating Scale (HDRS-17), and the Udvalg for Kliniske Undersøgelser (UKU) subscale was used for neurological/extrapyramidal side-effects. RESULTS: Thirty-four patients completed the trial. The mean dose of risperidone at endpoint was 2.8 mg/day. Last observation-carried-forward analysis showed significant reduction of YMRS scores from the first week of treatment, which continued until the endpoint (P<0.0001). At 6-month follow-up, 60% of patients were assymptomatic according to the CGI. The 32% who received risperidone in monotherapy seemed to respond equally well. Risperidone, as used in this study, appeared to be most protective against hypomanic than depressive recurrences. Nine patients (12%) had a depressive relapse during 6-month follow-up, one patient (2%) had an hypomanic relapse and another (2%) had both. No patients developed tardive dyskinesia during the duration of the study. Although most patients received risperidone in combination with standard mood-stabilizers, only three patients discontinued risperidone because of other side-effects. LIMITATIONS: In the absence of a placebo arm, it is uncertain to what extent the foregoing results could be ascribed to spontaneous remission of bipolar II disorder. CONCLUSIONS: Risperidone, either in combination with mood-stabilizers or alone was well-tolerated in bipolar II patients, who presented in a hypomanic state, and appeared efficacious. Further controlled research on the role of atypical antipsychotics in the treatment of less-than-manic forms of bipolar illness is warranted.

Alpha-1-acid glycoprotein in major depressive disorder. Relationships to severity, response to treatment and imipramine plasma levels.

BACKGROUND: Increased plasma levels of alpha-1-acid glycoprotein (AGP) were reported in major depressive disorder. However, the relationship between AGP levels, severity of depression, treatment response and antidepressant levels are still unclear. METHODS: Plasma AGP levels were measured in 36 subjects with major depressive disorder before and after a 6-week treatment with imipramine and in 30 controls. Free imipramine plasma levels of depressed patients were measured at 6 weeks. Comparative analysis between depressed patients and controls, between non-responders (N = 12) and responders (N = 24), and between severely depressed patients (N = 14) and moderately depressed patients (N = 22) were made. RESULTS: Depressed patients had significantly higher mean values of AGP than control subjects. Imipramine non-responders and specially severely depressed patients had significantly greater increases of AGP levels during treatment than other depressed subgroups. There was no correlation between baseline AGP levels and severity of depression or free imipramine levels. LIMITATIONS: The most significant limitations of this study are the small sample size and the fact that all the subjects were out-patients. Results should not be generalized to in-patient populations. CONCLUSIONS: Depressed patients showed high baseline concentrations of AGP. AGP levels did not predict either free imipramine plasma levels or differential response after 6 weeks of treatment with imipramine. A greater increase of AGP during treatment was associated with severity of depression and treatment non-response. CLINICAL IMPLICATIONS: The relationship between high plasma levels of AGP, severity of depression and lack of treatment response is clarified. The influence of imipramine levels is minimized.

Cognitive dysfunctions in recovered melancholic patients.

Cognitive dysfunctions were studied in symptom-free patients suffering from Recurrent Depressive Disorder with melancholia. Their performances on a standard neuropsychological battery were compared with those of a healthy sample matched for age and educational level. Statistically significant differences were found in Immediate Visual Memory, Delayed Logical and Visual Memory, Paired Learning and Block Design. Results seem to indicate that the cognitive disfunctions are not likely to be only mnesic. All these data suggest that these disfunctions found in some melancholic depressives could not be state-dependent.

Adjunctive gabapentin treatment of bipolar disorder.

INTRODUCTION: The aim of this study was to analyze the effectiveness of gabapentin administration to bipolar patients who had an incomplete response to other mood stabilizers. SUBJECTS AND METHODS: Twenty-two RDC bipolar 1 and II patients were assessed by means of the SADS and entered if they gave their consent to participate. All them had suffered from frequent relapses, subsyndromal features (mostly depressive) and incomplete response to other drugs. They all received open-label increasing doses of gabapentin until clinical response. The patients were assessed through the CGI-BP and a specific questionnaire at baseline and at 12 weeks of follow-up. RESULTS: Six out of the 22 patients dropped out for various reasons (four because of relapse, one because of side effects and one more because of poor compliance). Eight of the 16 patients that completed the 12-week follow-up showed at least two stages of improvement in the CGI. Using the last observation-carried forward analysis, the improvement was statistically significant for the depression subscale, and apparently related to social functioning, irritability and anxiety. Only one patient dropped out because of intolerance (mild rash). The mean dose of gabapentin was 1,310 mg/day. CONCLUSION: Gabapentin may be a useful drug for the add-on treatment of bipolar patients with poor response to other mood stabilizers. Gabapentin may improve depressive residual symptoms such as irritability, social withdrawal or anxiety. These results should be confirmed in randomized clinical trials.