F. Benedetti

Clock genes beyond the clock: CLOCK genotype biases neural correlates of moral valence decision in depressed patients.

Gene polymorphisms in the mammalian biological clock system influence individual rhythms. A single nucleotide polymorphism (SNP) in the 3′ flanking region of CLOCK (3111 T/C; rs1801260) influenced diurnal preference in healthy humans and caused sleep phase delay and insomnia in patients affected by bipolar disorder. Genes of the biological clock are expressed in many brain structures other than in the ‘master clock’ suprachiasmatic nuclei. These areas, such as cingulate cortex, are involved in the control of many human behaviors. Clock genes could then bias ‘nonclock’ functions such as information processing and decision making. Thirty inpatients affected by a major depressive episode underwent blood oxygen–level dependent (BOLD) functional magnetic resonance imaging (fMRI). The cognitive activation paradigm was based on a go/no‐go task. Morally connoted words were presented. Genotyping of CLOCK was performed for each patients. We measured activity levels through actimetry during the day before the fMRI study. CLOCK 3111 T/C SNP was associated with activity levels in the second part of the day, neuropsychological performance and BOLD fMRI correlates (interaction of genotype and moral valence of the stimuli). Our results support the hypothesis that individual clock genotype may influence several variables linked with human behaviors in normal and psychopathological conditions.

Temporal lobe grey matter volume in schizophrenia is associated with a genetic polymorphism influencing glycogen synthase kinase 3-β activity

At the crossroad of multiple pathways regulating trophism and metabolism, glycogen synthase kinase (GSK)3 is considered a key factor in influencing the susceptibility of neurons to harmful stimuli (neuronal resilience) and is a target for several psychiatric drugs that directly inhibit it or increase its inhibitory phosphorylation. Inhibition of GSK3 prevents apoptosis and could protect against the neuropathological processes associated with psychiatric disorders. A GSK3‐βpromoter single‐nucleotide polymorphism (rs334558) influences transcriptional strength, and the less active form was associated with less detrimental clinical features of mood disorders. Here we studied the effect of rs334558 on grey matter volumes (voxel‐based morphometry) of 57 patients affected by chronic schizophrenia. Carriers of the less active C allele variant showed significantly higher brain volumes in an area encompassing posterior regions of right middle and superior temporal gyrus, within the boundaries of Brodmann area 21. The temporal lobe is the brain parenchymal region with the most consistently documented morphometric abnormalities in schizophrenia, and neuropathological processes in these regions develop soon at the beginning of the illness. These results support the interest for GSK3‐βas a factor affecting neuropathology in major behavioural disorders, such as schizophrenia, and thus as a possible target for treatment.

White matter microstructure in bipolar disorder is influenced by the serotonin transporter gene polymorphism 5-HTTLPR†

Bipolar disorder (BD) is associated with signs of widespread disruption of white matter (WM) integrity. A polymorphism in the promoter of the serotonin transporter (5‐HTTLPR) influenced functional cortico‐limbic connectivity in healthy subjects and course of illness in BD, with the short (s) allele being associated with lower functional connectivity, and with earlier onset of illness and poor response to treatment. We tested the effects of 5‐HTTLPR on diffusion tensor imaging (DTI) measures of WM microstructure in 140 inpatients, affected by a major depressive episode in course of BD, of Italian descent. We used whole brain tract‐based spatial statistics in the WM skeleton with threshold‐free cluster enhancement of DTI measures of WM microstructure: axial, radial and mean diffusivity and fractional anisotropy. Compared with l/l homozygotes, 5‐HTTLPR*s carriers showed significantly increased radial and mean diffusivity in several brain WM tracts, including corpus callosum, cingulum bundle, uncinate fasciculus, corona radiata, thalamic radiation, inferior and superior longitudinal fasciculus and inferior fronto‐occipital fasciculus. An increase of mean and radial diffusivity, perpendicular to the main axis of the WM tract, is thought to signify increased space between fibers, thus suggesting demyelination or dysmyelination, or loss of bundle coherence. The effects of 5‐HTTLPR on the anomalous emotional processing in BD might be mediated by changes of WM microstructure in key WM tracts contributing to the functional integrity of the brain.

Infradian mood fluctuations during a Major Depressive episode

We investigated the predictability of infradian mood fluctuations during acute depressive episodes in patients affected by mood disorders. Previous findings showed that in a subgroup of patients the depressive symptomathology fluctuates with day-to-day changes which follow cyclical patterns (termed minicycles). We applied time series analysis, by means of autocorrelation techniques, to time lagged serial recordings of perceived mood levels of 22 inpatients (13 Major Depressive Recurrent and 9 Bipolar Depressive Disorders). Five patients (22.7%) were shown to exhibit predictable cyclical patterns in their perceived symptomathology, ranging in length from 6 to 14 days. Our study confirms the existence and the predictability, in a subgroup of patients, of cyclical mood patterns. Preliminary evidence suggests that patients with minicycles receive more medication changes than patients without, and thus that cyclical mood fluctuations strongly interacts with both the clinical decision making process and the outcome of acute depressive episodes.

Perceived mood and skin body temperature rhythm in depression

Abstract Eighteen inpatients affected by recurrent major depression were monitored in their clinical and biological features during the acute episode of illness. Diurnal mood variations rated with Visual Analogue Scale (VAS) and diurnal variations of skin body temperature were measured every 2 h consecutively for 2 days. Circadian rhythmicity of the two parameters was evaluated by cosinor analysis separately for each patient. The inspection of the individual cosine fitting shows that patients with a high circadian rhythmicity in perceived severity of symptomatology tend to show low circadian rhythmicity in skin body temperature, whereas patients with a low VAS oscillation tend to display a higher diurnal variation in skin body temperature. A chi-square test confirmed a statistical significance of the discordance between the two rhythms. We discuss our findings hypothesizing a different degree of entrainment of the disease process to the main circadian pacemaker.

P.1.119 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.

New Drugs in the Treatment of Borderline Personality Disorder

From both a clinical and a neurobiological point of view, Borderline Personality Disorder (BPD) as defined by DSM-IV (A.P.A., 1994) must be considered an heterogeneous condition. Clinical studies on BPD patients showed that BPD diagnosis is rarely the only Axis II diagnosis present in a personality disordered patient, and broadly overlaps with other diagnoses pertaining to the three DSM category clusters (e.g. Nurnberg et al., 1991). Moreover, comorbidity with Axis I pathologies is often present: as reported in DSM-IV itself, heterogenous Axis I pathologies (such as mood disorders, substance-related disorders, eating disorders, post-traumatic stress disorders, and attention-deficit disorder) are commonly diagnosed in patients affected by BPD.