Patricio Molero

Clinical involvement of catechol-O-methyltransferase polymorphisms in schizophrenia spectrum disorders: influence on the severity of psychotic symptoms and on the response to neuroleptic treatment

Genetic variation in the catechol-O-methyltransferase (COMT) gene may influence the susceptibility to schizophrenia and the response to neuroleptic treatment. The authors tested for an association between a COMT haplotype and schizophrenia-spectrum disorders and for an eventual influence of a specific COMT genotype in the clinical outcome and in the response to treatment. The genotypes for single nucleotide polymorphisms rs737865, rs4633, rs6267, rs4680 (Val158Met) and rs165599 were determined in 207 patients with schizophrenia-spectrum disorders and 204 paired controls. Statistical tests for linkage disequilibrium and for case–control differences in haplotype frequencies were performed using log-linear modelling embedded within the expectation-maximization algorithm. P-values based on permutations were calculated using the software UNPHASED, and odds ratios were estimated using the SHEsis platform. The response to neuroleptic treatment was assessed by the Global Assessment of Functioning scale and the severity of psychotic symptoms by the positive and negative syndrome scale (PANSS) scale. The overall disease status was significantly associated with the T-G (Val) diplotype for rs4633–rs4680 (P=0.0049). A significant association was observed between schizophrenia, but not other related disorders, and genotypes GG (Val/Val) for rs4680 and TT for rs4633. Val/Val patients with schizophrenia showed a higher severity of the psychotic symptoms and a worse response to the neuroleptic treatment. COMT genetic variation seems to be involved in the psychotic symptomatology of the schizophrenia-spectrum disorders and specifically in the narrow schizophrenia phenotype. Our results show an influence of the Val158Met polymorphism on the severity of psychotic symptoms and on the response to treatment.

Time perception networks and cognition in schizophrenia: A review and a proposal

Timing is an essential function for the survival of many living organisms. Despite its significance, it is relatively under-researched, particularly in schizophrenia. We examined neurophysiological, neuropathological, imaging and genetic studies of both healthy subjects and subjects suffering from schizophrenia in relation to time perception as measured by interval timing. We found that the data from studies in healthy populations indicate that time perception may be inter-linked with numerous other cognitive functions and share common brain networks. The same networks are implicated in the pathophysiology of schizophrenia. There is also evidence that several neurotransmitter systems, particularly the dopaminergic D2 system, are involved in interval timing. Patients with schizophrenia have been shown to suffer from a distorted sense of time, which has an impact on their cognitive function and results in both positive and negative symptoms. Therefore, genes involved in interval timing can be considered candidate genes for distorted cognition in schizophrenia. We discuss the hypothesis that time perception dysfunction is a primary cognitive dysfunction in schizophrenia.

Diet quality and depression risk: A systematic review and dose-response meta-analysis of prospective studies

BACKGROUND It has been claimed that the quality of a diet is associated with the incidence of depressive disorders. We sought to investigate the evidence for this claim. METHODS Systematic searches were performed up to March 6th, 2017 in order to identify prospective cohort studies that reported on exposure to dietary patterns or food groups and the incidence of depression/depressive symptoms. Data from 24 independent cohorts (totalling 1,959,217 person-years) were pooled in random-effects meta-analyses. RESULTS Adherence to a high-quality diet, regardless of type (i.e., healthy/prudent or Mediterranean), was associated with a lower risk of depressive symptoms over time (odds ratios ranged 0.64-0.78 in a linear dose-response fashion [P < 0.01]). A relatively low dietary inflammatory index was also associated with a somewhat lower incidence of depressive symptom (odds ratio = 0.81), although not in a dose-response fashion. Similar associations were found for the consumption of fish and vegetables (odds ratios 0.86 and 0.82 respectively) but not for other high quality food groups (e.g., fruit). Studies that controlled for depression severity at baseline or that used a formal diagnosis as outcome did not yield statistically significant findings. Adherence to low quality diets and food groups was not associated with higher depression incidence. LIMITATIONS Our ability to detect confounders was only limited. CONCLUSION There is evidence that a higher quality of a diet is associated with a lower risk for the onset of depressive symptoms, but not all available results are consistent with the hypothesis that diet influences depression risk. Prospective studies that control for relevant confounders such as obesity incidence and randomized controlled prevention trials are needed to increase the validity of findings in this field.

Catechol-O-Methyltransferase Val158Met Polymorphism and Clinical Response to Antipsychotic Treatment in Schizophrenia and Schizo-Affective Disorder Patients: a Meta-Analysis

Background: The catechol-O-methyltransferase (COMT) enzyme plays a crucial role in dopamine degradation, and the COMT Val158Met polymorphism (rs4680) is associated with significant differences in enzymatic activity and consequently dopamine concentrations in the prefrontal cortex. Multiple studies have analyzed the COMT Val158Met variant in relation to antipsychotic response. Here, we conducted a meta-analysis examining the relationship between COMT Val158Met and antipsychotic response. Methods: Searches using PubMed, Web of Science, and PsycInfo databases (03/01/2015) yielded 23 studies investigating COMT Val158Met variation and antipsychotic response in schizophrenia and schizo-affective disorder. Responders/nonresponders were defined using each study’s original criteria. If no binary response definition was used, authors were asked to define response according to at least 30% Positive and Negative Syndrome Scale score reduction (or equivalent in other scales). Analysis was conducted under a fixed-effects model. Results: Ten studies met inclusion criteria for the meta-analysis. Five additional antipsychotic-treated samples were analyzed for Val158Met and response and included in the meta-analysis (ntotal=1416). Met/Met individuals were significantly more likely to respond than Val-carriers (P=.039, ORMet/Met=1.37, 95% CI: 1.02–1.85). Met/Met patients also experienced significantly greater improvement in positive symptoms relative to Val-carriers (P=.030, SMD=0.24, 95% CI: 0.024–0.46). Posthoc analyses on patients treated with atypical antipsychotics (n=1207) showed that Met/Met patients were significantly more likely to respond relative to Val-carriers (P=.0098, ORMet/Met=1.54, 95% CI: 1.11–2.14), while no difference was observed for typical-antipsychotic-treated patients (n=155) (P=.65). Conclusions: Our findings suggest that the COMT Val158Met polymorphism is associated with response to antipsychotics in schizophrenia and schizo-affective disorder patients. This effect may be more pronounced for atypical antipsychotics.

Relationship between adherence to Dietary Approaches to Stop Hypertension (DASH) diet indices and incidence of depression during up to 8 years of follow-up.

OBJECTIVE Our aim was to evaluate the relationship between adherence to different Dietary Approaches to Stop Hypertension (DASH) diet indices and the risk of depression. DESIGN In a prospective study we assessed 14051 participants of a dynamic (permanently ongoing recruitment) prospective cohort (the Seguimiento Universidad de Navarra (SUN) Project), initially free of depression. At baseline, a validated FFQ was used to assess adherence to four previously proposed DASH indices (Dixon, Mellen, Fung and Günther). To define the outcome we applied two definitions of depression: a less conservative definition including only self-reported physician-diagnosed depression (410 incident cases) and a more conservative definition that required both clinical diagnosis of depression and use of antidepressants (113 incident cases). Cox regression and restricted cubic splines analyses were performed. RESULTS After a median follow-up period of 8 years, the multiple-adjusted model showed an inverse association with the Fung DASH score (hazard ratio (HR)=0·76; 95 % CI 0·61, 0·94) when we used the less conservative definition of depression, and also under the more conservative definition (HR=0·63; 95 % CI 0·41, 0·95). We observed a weak inverse association with the Mellen DASH score, but no statistically significant association was found for the other definitions. The restricted cubic splines analyses suggested that these associations were non-linear (U-shaped). CONCLUSIONS Moderate adherence to the DASH diet as operationalized by Fung and Mellen was related to lower depression risk. Since these associations were non-linear, additional prospective studies are required before the results can be generalized and clinical recommendations can be given.

The influence of the COMT genotype in the underlying functional brain activity of context processing in schizophrenia and in relatives

UNLABELLED Context processing deficits have been shown to be present in chronic and first episode schizophrenia patients and in their relatives. This cognitive process is linked to frontal functioning and is highly dependent on dopamine levels in the prefrontal cortex (PFC). The catechol-O-methyltransferase (COMT) enzyme plays a prominent role in regulating dopamine levels in PFC. Genotypic variations in the functional polymorphism Val(158)Met COMT appear to have an impact in dopamine signaling in the PFC of healthy subjects and schizophrenia patients. We aimed to explore the effect of the Val(158)Met COMT polymorphism on brain activation during the performance of a context processing task in healthy subjects, schizophrenia spectrum patients and their healthy relatives. METHODS 56 participants performed the Dot Probe Expectancy task (DPX) during the fMRI session. Subjects were genotyped and only the Val and Met homozygotes participated in the study. RESULTS Schizophrenia spectrum patients and their relatives showed worse performance on context processing measures than healthy control subjects. The Val allele was associated with more context processing errors in healthy controls and in relatives compared to patients. There was a greater recruitment of frontal areas (supplementary motor area/cingulate gyrus) during context processing in patients relative to healthy controls. Met homozygotes subjects activated more frontal areas than Val homozygotes subjects. CONCLUSIONS The Val(158)Met COMT polymorphism influences context processing and on its underlying brain activation, showing less recruitment of frontal areas in the subjects with the genotype associated to lower dopamine availability in PFC.

Cardiovascular risk and incidence of depression in young and older adults: evidence from the SUN cohort study

ANCOVA analysis, which included age and education as covariates. The model also remained significant in a follow-up analysis in which participants who identified as AfricanAmerican (N515) were excluded. Carriers of the 5HTTLPR-S’ allele had increased PTSD symptoms compared to individuals homozygous for the L’ allele (IES mean score: L’L’547.3 6 5.3, S559.8 6 4.1). For DISC1, individuals homozygous for the T allele had increased PTSD symptoms compared to A carriers (A545.3 6 2.8, TT561.9 6 7.2). In ANCOVA analysis of symptom sub-factors, 5-HTTLPR and DISC1 selectively influenced intrusion and hypervigilance symptoms, but did not affect avoidance symptoms. PTSD symptom severity (total IES scores) increased by an average of 40% with each risk genotype (none538.4, one5 54.5, two565.6). These data support prior observations of 5-HTTLPR effects on PTSD symptoms in military veterans. Although 5-HTTLPR has been identified as a potential contributor to PTSD susceptibility in civilian-based populations, its effect may be less robust in those populations, due to lower overall level of trauma exposure. The effects of 5-HTTLPR on PTSD in military veterans after deployment to a war zone may be more robust because of a universal and constant exposure to threat, military training, and/or separation from family and home social support. In addition to 5-HTTLPR, genetic variation in DISC1, a gene associated with susceptibility to multiple mental disorders, was found to contribute to PTSD symptom severity. Possessing both DISC1 and 5-HTTLPR risk genotypes resulted in a 1.7fold increase in PTSD symptoms. Although this is the first report of DISC1 S704C TT allele as a risk factor for PTSD, the finding is not surprising, considering that this allele has been identified as a risk factor for major depression. DISC1 variants interfere with a protein complex important for organelle transport and in tethering of mitochondria, interfering with dendritic development and reducing densities of dendritic spines in the frontal cortex, paralleling our recent report of spine density reductions in the frontal cortex in PTSD. This study was powered to screen for candidate genes with relatively large effect sizes on PTSD symptoms in combat veterans, which may be different from sets of genes affecting PTSD in civilian populations. Study of the serotonin system in PTSD is motivated in large part by the therapeutic utility of serotonin uptake inhibitors to treat symptoms of PTSD. Our data provide additional impetus for continued study of this system in PTSD pharmacotherapy. In addition, antipsychotics such as risperidone have been shown to reverse DISC1-related behavioral deficits and pathophysiology in animal models, suggesting the possibility that such agents could be re-examined for use as alternative pharmacotherapies for PTSD. Keith A. Young, Sandra B. Morissette, Robert Jamroz, Eric C. Meyer, Matthew S. Stanford, Li Wan, Nathan A. Kimbrel Central Texas Veterans Health Care System, Temple, TX, USA; Department of Veterans Affairs VISN 17 Center of Excellence for Research on Returning War Veterans, Waco, TX, USA; Department of Psychiatry and Behavioral Science, Texas A&M Health Science Center, Temple, TX, USA; University of Texas at San Antonio, San Antonio, TX, USA; Hope and Healing Center & Institute, Houston, TX, USA; Durham Veterans Affairs Medical Center, Durham, NC, USA; VA Mid-Atlantic Mental Illness Research, Education, and Clinical Center, Durham, NC, USA; Duke University Medical Center, Durham, NC, USA

Intake of High-Fat Yogurt, but Not of Low-Fat Yogurt or Prebiotics, Is Related to Lower Risk of Depression in Women of the SUN Cohort Study

BACKGROUND Yogurt and prebiotic consumption has been linked to better health. However, to our knowledge, no longitudinal study has assessed the association of yogurt and prebiotic consumption with depression risk. OBJECTIVE We longitudinally evaluated the association of yogurt and prebiotic consumption with depression risk in a Mediterranean cohort. METHODS The SUN (Seguimiento Universidad de Navarra) Project is a dynamic, prospective cohort of Spanish university graduates. A total of 14,539 men and women (mean age: 37 y) initially free of depression were assessed during a median follow-up period of 9.3 y. Validated food-frequency questionnaires at baseline and after a 10-y follow-up were used to assess prebiotic (fructans and galacto-oligosaccharide) intake and yogurt consumption (<0.5, ≥0.5 to <3, ≥3 to <7, and ≥7 servings/wk). Participants were classified as incident cases of depression when they reported a new clinical diagnosis of depression by a physician (previously validated). Multivariable Cox proportional hazards models were used to calculate HRs and 95% CIs. RESULTS We identified 727 incident cases of depression during follow-up. Whole-fat yogurt intake was associated with reduced depression risk: HR for the highest [≥7 servings/wk (1 serving = 125 g)] compared with the lowest (<0.5 servings/wk) consumption: 0.78 (95% CI: 0.63, 0.98; P-trend = 0.020). When stratified by sex, this association was significant only in women (HR: 0.66; 95% CI: 0.50, 0.87; P-trend = 0.004). Low-fat yogurt consumption was associated with a higher incidence of depression (HR: 1.32; 95% CI: 1.06, 1.65; P-trend = 0.001), although this association lost significance after the exclusion of early incident cases, suggesting possible reverse causation bias. Prebiotic consumption was not significantly associated with depression risk. CONCLUSIONS Our study suggests that high consumption of whole-fat yogurt was related to a lower risk of depression in women of the SUN cohort. No association was observed for prebiotics. Further studies are needed to clarify why the yogurt-depression association may differ by fat content of the yogurt.

A Schizophrenia-Like Psychotic Disorder Secondary to an Arachnoid Cyst Remitted with Neurosurgical Treatment of the Cyst

We describe a case of delusional psychosis that was terminated by neurosurgical removal of a large arachnoid cyst. The patient was suffering his first psychotic episode and had symptoms typical of schizophrenia. The case underscores the importance of considering that an arachnoid cyst can induce psychopathological symptoms, even those of schizophrenia. Indeed, such symptoms may be the cysts only clinical manifestation. In addition, the case highlights the importance of doing a structural imaging test when confronted with a first episode of psychosis, especially if the episode is relatively late in appearance. Such imaging may lead to a diagnosis that in turn can enable a definitive neurosurgical resolution of the psychosis.

Stability of sex differences by diagnosis in psychiatric hospitalizations

We examined sex differences in the distribution of psychiatric diagnoses among hospitalized patients, controlling for socio-demographic variables. The sample included 1865 psychiatric inpatients consecutively admitted during a 9-year period. The finding of a higher proportion of men among patients hospitalized for schizophrenia or substance use disorder and a higher proportion of women among those admitted for affective disorders, including bipolar disorder, was stable over time. A better understanding of these differences may help to establish more effective treatment strategies.