E. Marino

A length polymorphism in the circadian clock gene Per3 influences age at onset of bipolar disorder

Age at onset of bipolar disorder might represent the penetrance of the system for specific genetic liability involved in the genesis of the illness. Genetic factors influencing age at onset have been shown to play a role in shaping core characteristics of the illness, such as severity and pattern of recurrence. Genetic variants of genes regulating the circadian clock could contribute to define endophenotypes of bipolar disorder, and have been associated with clinical features of the disease. The coding region of Per3 gene contains a variable-number tandem-repeat (VNTR) polymorphism which has been associated with diurnal preference, sleep structure and sleep homeostasis in healthy subjects. In a homogeneous sample of 99 patients affected by bipolar disorder type I we observed that Per3 VNTR influenced age at onset of illness: earlier age at onset in homozygote carriers of Per35 variant, later in homozygotes for Per34, and intermediate in heterozygotes. Allele frequencies were not significantly different from those reported in healthy subjects. Results need to be confirmed in larger samples, but warrant interest for the variants of molecular clock genes as possible endophenotypes of bipolar disorder.

Influence of catechol-O-methyltransferase Val158Met polymorphism on neuropsychological and functional outcomes of classical rehabilitation and cognitive remediation in schizophrenia.

Neurocognitive deficits are recognized as core features of schizophrenia and have a great impact on functional outcome. Recent reports have suggested that a functional polymorphism, Val158Met, of the catechol-O-methyltransferase (COMT) gene, partially influences cognitive performances (mainly cognitive flexibility and working memory) both in schizophrenic patients and in healthy controls, probably by modulating prefrontal dopamine function. While previous studies focused on single evaluation of cognitive functioning, we aimed to analyse the additive effect of COMT genotype and cognitive exercise on dynamic modulation of cognitive performances. We analysed the COMT Val158Met polymorphism in 50 patients with chronic schizophrenia randomly allocated to two treatment conditions for 3 months: standard rehabilitation treatment (SRT) alone and SRT plus specific cognitive exercise of impaired functions. We then divided our sample in four subgroups on the basis of genotype (Val/Val versus Met carriers) and treatment (placebo versus active). We assessed patients with a neuropsychological battery, the Positive and Negative Symptoms Scale (PANSS) and the Quality of Life Scale (QLS) at enrolment, after 3 months of therapy and after further 3 months of follow-up. We found significantly greater improvement of cognitive flexibility performance and QLS total score for Met carriers on active treatment in comparison to Val/Val on placebo. The findings support the hypothesis that COMT polymorphism influences individual capacity to recover from cognitive deficit through rehabilitation therapy after a wider intervention also including deficit-specific cognitive exercise as a potentiating tool.

Interaction between SERTPR and stressful life events on response to antidepressant treatment

A polymorphism within the serotonin transporter gene (SERTPR) has been repeatedly associated to mood disorders and response to SSRIs treatment. Recent evidence suggested that influence of genetic effect of SERTPR might be modulated by stress, particularly as regard the development of anxious-depressive symptoms. Nevertheless, there is no information about the role of stressors as potential modulator of SERTPR effects on depressive outcome during pharmacological treatment. In a sample of 159 mood disorder patients treated with fluvoxamine, we found stressors preceding the onset of the illness significantly influencing the genetic effect exerted by SERTPR on response after 6 weeks of treatment. This preliminary finding supports the idea of complex interaction between biological and environmental factors underlying the efficacy of biological treatments, other than liability for mood disorders. Nevertheless, many limitations characterize the present investigation and well-funded studies on larger samples are required.

HTTLPR functional polymorphism in schizophrenia: Executive functions vs. sustained attention dissociation

BACKGROUND Recently attention has been addressed to the role of 5-HT in cognition and several experimental studies revealed that manipulations of the central 5-HT system can produce quite specific changes in cognitive functioning. These results may suggest new treatment strategies to improve cognition in psychiatric conditions characterized by neuropsychological impairments, such as schizophrenia. It is possible to investigate the involvement of 5-HT in cognition by examining the impact of genetic variation in key regulators of serotoninergic neurotransmission. Among these, the serotonin transporter (5-HTT) presents a functional polymorphism in the transcriptional control region of the gene (5-HTTLPR) affecting transcriptional efficiency. In the present study, we aimed to analyze the effect of 5-HTTLPR polymorphism on specific cognitive functions, known to be affected by 5-HT manipulation and altered in schizophrenia. METHODS 223 schizophrenia patients were tested with Wisconsin Card Sorting Test (WCST), for the evaluation of cognitive flexibility, Continuous Performance Test (CPT), for the evaluation of attention, and genotyped for the 5-HTTLPR. RESULTS We found a significant association between HTT polymorphism and executive functions and inversely with sustained attention. The presence of the high-activity long (L) allele in homozygosis was a predictor of better executive performances and poorer performances of attention. CONCLUSIONS Our findings suggest that factors affecting serotonin availability may play a specific role in cognitive processes, probably through complex modulation of the different performance components.

Serotonin 5-HT2A receptor gene variants influence antidepressant response to repeated total sleep deprivation in bipolar depression.

5-HT2A receptor density in prefrontal cortex was associated with depression and suicide. 5-HT2A receptor gene polymorphism rs6313 was associated with 5-HT2A receptor binding potential, with the ability of individuals to use environmental support in order to prevent depression, and with sleep improvement after antidepressant treatment with mirtazapine. Studies on response to antidepressant drugs gave inconsistent results. Here we studied the effect of rs6313 on response to repeated total sleep deprivation (TSD) in 80 bipolar depressed inpatients treated with three consecutive TSD cycles (each one made of 36 h awake followed by a night of undisturbed sleep). All genotype groups showed comparable acute effects of the first TSD, but patients homozygotes for the T variant had better perceived and observed benefits from treatment than carriers of the C allele. These effects became significant after the first recovery night and during the following days, leading to a 36% higher final response rate (Hamilton depression rating<8). The higher density of postsynaptic excitatory 5-HT2A receptors in T/T homozygotes could have led to higher behavioural effects of increased 5-HT neurotransmission due to repeated TSD. Other possible mechanisms involve allostatic/homeostatic adaptation to sleep loss, and a different effect of the allele variants on epigenetic influences. Results confirm the interest for individual gene variants of the serotonin pathway in shaping clinical characteristics of depression and antidepressant response.

Serotonin transporter and saitohin genes in risk of Alzheimer’s disease and frontotemporal lobar dementia: preliminary findings

Serotonergic transmission impairment and abnormal phosphorylation of tau protein have been implicated in the physiopathology of Alzheimer’s disease (AD) and frontotemporal lobar dementia (FTLD). Associations between a functional polymorphism (5-HTTLPR), in the promoter region of the serotonin transporter gene, and susceptibility to sporadic AD and FTLD have been reported. A polymorphism (Q7R) in saitohin gene inside the microtubule-associated protein tau gene has also been related to dementia. To determine the possible role of the two polymorphisms in susceptibility to AD and FTLD, we performed a case–control study collecting 218 Italian sporadic dementia patients and 54 controls. We found a significant excess of 5-HTTLPR short alleles and an interaction between 5-HTTLPR and Q7R polymorphisms in demented subjects. Our study confirms the role of 5-HTTLPR as a potential susceptibility factor for sporadic dementia in the Italian population, and suggests a possible interaction between 5-HTTLPR and Q7R polymorphisms in neurodegenerative diseases.

Genetic bases of comorbidity between mood disorders and migraine: possible role of serotonin transporter gene

Migraine is a common neurological disease in the population and the most associated headache with mood disorder. Although the relationship between migraine and depression is well known, the reverse correlation between depression and migraine was observed but not well understood. The tight relationship between the two disturbances is also suggested by the efficacy of antidepressants for migraine treatment. Starting from these observations, we can presume that both migraine and depression have overlapping biological bases. The main target of antidepressant treatments belonging to the serotonin selective reuptake inhibitors (SSRI) type is the serotonin transporter (SERT); a well-studied polymorphic variant, in the promoter region of the gene (SERTPR), has been demonstrated to influence the availability of serotonin in the synaptic cleft. So, our group studied the possible role of the SERT as a risk factor, both for migraine and mood disorders, in a sample of 96 patients affected by both pathologies.

Schizophrenia: genetics, prevention and rehabilitation

Objective: Genetic factors are largely implicated in predisposing to schizophrenia. Environmental factors contribute to the onset of the disorder in individuals at increased genetic risk. Cognitive deficits have emerged as endophenotypes and potential therapeutic targets for schizophrenia because of their association with functional outcome. The aims of this review were to analyse the joint effect of genetic and environmental (G×E) factors on liability to schizophrenia and to investigate relationships between genes and cognitive endophenotypes focusing on practical applications for prevention and rehabilitation. Methods: Medline search of relevant studies published between 1990 and 2008. Results: In schizophrenia, examples of G×E interaction include the catechol-O-methyl transferase (COMT) (Val158Met) polymorphism, which was found to moderate the onset of psychotic manifestations in response to stress and to increase the risk for psychosis related to cannabis use, and neurodevelopmental genes such as AKT1 (serine-threonine kinase), brain-derived neurotrophic factor (BDNF), DTNBP1 (dysbindin) and GRM3 (metabotropic glutamate receptor 3), which were associated with development of schizophrenia in adulthood after exposure to perinatal obstetric complications. Neurocognitive deficits are recognised as core features of schizophrenia that facilitate the onset of the disorder and have a great impact on functional outcome. Neurocognitive deficits are also endophenotypes that have been linked to a variety of genes [COMT, neuregulin (NRG1), BDNF, Disrupted-In-Schizophrenia 1 (DISC1) and dysbindin] conferring susceptibility to schizophrenia. Recently, it has emerged that cognitive improvement during rehabilitation therapy was under control of COMT (Val158Met) polymorphism. Conclusion: This review could indicate a pivotal role of psychiatric genetics in prevention and rehabilitation of schizophrenic psychoses.

Searching Susceptibility Loci for Bipolar Disorder: A Sib Pair Study on Chromosome 12

Background/Aims: Several linkage studies demonstrated that different chromosomal regions are involved in the susceptibility to bipolar disorder. In particular, some genome scans evidenced the role of chromosome 12. For this reason, our group chose this chromosome for a preliminary genome scan on a sample of 137 Italian sib pairs, including at least 1 bipolar subject. Methods: The analyses were carried out by means of DNA extracted from whole blood. DNA samples were genotyped by 19 simple tandem repeat markers (microsatellites). Starting from the genetic data, we performed two- and multipoint linkage analyses (both parametric and nonparametric) by means of Easy Linkage plus package (version 5.05). Results: The multipoint linkage analyses pointed out a region suggestive of linkage between the markers D12S310 and D12S364, at locus 12p12. In particular, we reached the best evidence of linkage performing multipoint analyses and assuming a recessive model, under the hypothesis of genetic heterogeneity (heterogeneity LOD score = 2.01 and α = 0.77). Conclusion: It is interesting to notice that the region at the marker D12S364 is located inside the gene coding for the glutamatergic receptor GRIN2B. Therefore, our finding not only confirmed the role of genetics in determining liability to bipolar disorder, but suggested glutamatergic transmission impairment as a possible cause. Nevertheless, we acknowledge that our study is heavily underpowered. Therefore, independent replication is needed.

P.2.a.012 Genetic bases of comorbidity between mood disorders and migraine: possible role of serotonin transporter gene

Migraine is a common neurological disease in the population and the most associated headache with mood disorder. Although the relationship between migraine and depression is well known, the reverse correlation between depression and migraine was observed but not well understood. The tight relationship between the two disturbances is also suggested by the efficacy of antidepressants for migraine treatment. Starting from these observations, we can presume that both migraine and depression have overlapping biological bases. The main target of antidepressant treatments belonging to the serotonin selective reuptake inhibitors (SSRI) type is the serotonin transporter (SERT); a well-studied polymorphic variant, in the promoter region of the gene (SERTPR), has been demonstrated to influence the availability of serotonin in the synaptic cleft. So, our group studied the possible role of the SERT as a risk factor, both for migraine and mood disorders, in a sample of 96 patients affected by both pathologies.