Adele Pirovano

Genetic dissection of psychopathological symptoms: Insomnia in mood disorders and CLOCK gene polymorphism

We investigated the possible effect of the 3111T/C CLOCK gene polymorphism on sleep disorders in a sample of 620 patients affected by major depressive disorder (MDD) and bipolar disorder (BP). We detected a significantly higher recurrence of initial (P = 0.0001), middle (P = 0.0009), and early (P = 0.0008) insomnia in homozygotes for the C variant and a similar trend concerning decreased need of sleep in BP (P = 0.0074). Other demographic and clinical features were found not related with CLOCK polymorphisms. This preliminary observation leads to hypothesize a possible involvement of the CLOCK gene polymorphism in the sleep disregulations in MDD and BP. Copyright

The C(–1019)G polymorphism of the 5-HT1A gene promoter and antidepressant response in mood disorders: preliminary findings

Several studies have demonstrated the involvement of 5-HT1A receptors in the pathogenesis of depression and in the antidepressant response to SSRIs. A functional new variant in the promoter region of the 5-HT1A gene was recently reported (-1019 C>G). The aim of this study is to investigate a possible association between this 5-HT1A receptor variant and antidepressant response to fluvoxamine in a sample of 262 mood-disorder subjects (151 major depressed and 111 bipolars) treated with fluvoxamine for 6 wk. The severity of depressive symptoms was assessed weekly with the Hamilton Rating Scale for Depression (HAMD). 5-HT1A variants did not influence antidepressant response in the whole sample and in unipolar subjects. In bipolars, 5-HT1A*C/C genotype carriers showed a better response to fluvoxamine (p=0.036), independently from clinical variables. The 5-HT1A polymorphism effect on antidepressant response was independent from the previously reported effect of the 5-HTTLPR polymorphism. In conclusion, 5-HT1A variants could influence the antidepressant efficacy in bipolar subjects, even if results must be verified on larger samples.

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.

SSRIs antidepressant activity is influenced by Gβ3 variants

Abstract The aim of the present study was to test a possible effect of the G-protein β3-subunit (Gβ3) C825T gene variant on the antidepressant activity of selective serotonin reuptake inhibitors (SSRIs) in a sample of major and bipolar depressives, with or without psychotic features. Four hundred and ninety inpatients were treated with fluvoxamine 300 mg/day ( n =362) or paroxetine 40 mg/day ( n =128) and either placebo or pindolol in a double-blind design for 6 weeks. The severity of depressive symptoms was weekly assessed with the Hamilton Rating Scale for Depression. Gβ3 allelic variants were determined in each subject using a PCR-based technique. Subjects with Gβ3 T/T variants showed better response to treatment ( P =0.009) and this effect was independent from analyzed demographic and clinical variables. These results confirm preliminary reports and shed further light on the genetics of the response to antidepressant treatments.

Lithium and GSK3-β Promoter Gene Variants Influence White Matter Microstructure in Bipolar Disorder

Lithium is the mainstay for the treatment of bipolar disorder (BD) and inhibits glycogen synthase kinase 3-β (GSK3-β). The less active GSK3-β promoter gene variants have been associated with less detrimental clinical features of BD. GSK3-β gene variants and lithium can influence brain gray matter structure in psychiatric conditions. Diffusion tensor imaging (DTI) measures of white matter (WM) integrity showed widespred disruption of WM structure in BD. In a sample of 70 patients affected by a major depressive episode in course of BD, we investigated the effect of ongoing long-term lithium treatment and GSK3-β promoter rs334558 polymorphism on WM microstructure, using DTI and tract-based spatial statistics with threshold-free cluster enhancement. We report that the less active GSK3-β rs334558*C gene-promoter variants, and the long-term administration of the GSK3-β inhibitor lithium, were associated with increases of DTI measures of axial diffusivity (AD) in several WM fiber tracts, including corpus callosum, forceps major, anterior and posterior cingulum bundle (bilaterally including its hippocampal part), left superior and inferior longitudinal fasciculus, left inferior fronto-occipital fasciculus, left posterior thalamic radiation, bilateral superior and posterior corona radiata, and bilateral corticospinal tract. AD reflects the integrity of axons and myelin sheaths. We suggest that GSK3-β inhibition and lithium could counteract the detrimental influences of BD on WM structure, with specific benefits resulting from effects on specific WM tracts contributing to the functional integrity of the brain and involving interhemispheric, limbic, and large frontal, parietal, and fronto-occipital connections.

How do genes exert their role? Period 3 gene variants and possible influences on mood disorder phenotypes

The action of multiple liability genes is responsible for complex phenotypes at the same time, a single gene, could control several phenotypic features. This is the case of human period 3 gene (hper3), mainly involved in the setting of the biologic clock. Some variants of this gene, besides being associated with the Delayed Sleep Phase Syndrome, showed a key role in determining evening preference rather than morning one. According to this rationale, we hypothesized that this gene could influence circadian mood fluctuations, in mood disorders. Our study demonstrated that rare genetic variants of hper3 are significantly associated to a number of mood disorders features, such as age of onset, response to SSRIs treatment, circadian mood oscillations and characteristics of temperament. These preliminary results could shed further light on the involvement of circadian genes in various aspects of physiological and psychopathological mechanisms of the brain.

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.

Circadian clock gene Per3 variants influence the postpartum onset of bipolar disorder

Postpartum depression can mark the onset of bipolar disorder. The coding region of Per3 gene contains a variable-number tandem-repeat polymorphism, which has been shown to influence bipolar disorder onset and to affect breast cancer risk. We showed a relationship between Per3 polymorphism and postpartum depressive onset in bipolar disorder.

Gene–gene interaction of glycogen synthase kinase 3-β and serotonin transporter on human antidepressant response to sleep deprivation

BACKGROUND Glycogen synthase kinase 3-β (GSK3-β) is involved in the control of cell behavior and in the mechanism of action of lithium and serotonergic antidepressants, and in humans a promoter variant (rs334558*C) was associated with reduced activity and better antidepressant response. The short form of a polymorphism in the promoter in the serotonin transporter (5-HTTLPR) has been consistently associated with worse antidepressant response. In animals the knockout of GSK3-β counteracts the depressive-like behavioral effects of 5-HT inhibition. METHODS With a translational approach, we studied the effect of 5-HTTLPR and rs334558 on antidepressant response to sleep deprivation in a unique sample of 122 patients affected by a major depressive episode in course of bipolar disorder. Mood was self rated on Visual Analog Scales, and severity of depression was rated on Montgomery-Asberg rating scale. RESULTS We observed a triple interaction of 5-HTTLPR, rs334558 and treatment on severity of depression. While among rs334558 T/T homozygotes the best antidepressant response was associated with 5-HTTLPR l/l homozygosity, among the rs334558 C carriers the 5-HTTLPR s/s showed the best response to treatment. CONCLUSIONS A gene promoter polymorphism which reduces the activity of GSK3-β counteracts the detrimental influence of the short form of the 5-HT promoter on antidepressant response. A key component of Wnt pathway, and upstream of the mTOR signaling cascade, GSK3-β influences synaptic plasticity and cell resilience. Gene-gene interactions between components of the monoaminergic signal transduction pathways and of plasticity related pathways can shape the individual antidepressant response.

Role of serotonergic gene polymorphisms on response to transcranial magnetic stimulation in depression

Transcranial magnetic stimulation (TMS) has been extensively studied as a treatment for Major Depression. However, no data are available about the role of genetic variables on the response to this treatment. We analysed the role of two polymorphisms that influence the response to antidepressants: the polymorphisms of the serotonin transporter promoter region (SERTPR) and of the 5-HT(1A) serotonergic receptor promoter region (-1019C/G). Ninety-nine patients from two double-blind, randomised, sham-controlled TMS trials were enrolled. There was a significant influence (p=0.016) of the SERTPR polymorphism on treatment outcome, without differences between active and sham stimulation. Conversely, there was a significant (p=0.014) interaction between 5-HT(1A) genotype and type of stimulation: C/C patients showed a higher difference between active and sham stimulation, indicating that these patients benefited more by TMS than C/G and G/G subjects. Our sample has not the power to control for the possible influence of different medications on these results.