Psychiatry


Enrico Smeraldi

Polygenic analysis on major psychoses symptomatology
Strong evidences suggest that genetic factors play a substantial role in the development of major psychoses (schizophrenia and mood disorders). However, despite decades of efforts, up to now no unequivocal liability gene has been reported. Two are the possible reasons for this failure: the complex transmission model and the clinical presentation of these disorders. Transmission model analyses suggest that 4 to 12 interacting genes may be responsible for the diseases. The clinical manifestation is extremely heterogeneous, ranging from moderate to very severe symptomatology; then, the traditional classification may be not adequate for genetic studies. We have therefore developed and validated a phenotype definition independent from diagnoses and based on the whole psychiatric symptomatology. Subjects are therefore no longer defined by diagnoses, but by severity of their lifetime symptoms. Using this approach, we identified an association between DRD4*7 (exon 3) and delusional symptomatology in a sample of 461 subjects affected by major psychoses and we confirmed the finding in a sample of mood disorder subjects. We reported also possible liability genes for depressive and disorganized symptomatology.


Psychopatology of major psychoses
We studied the symptomatological presentation of major psychoses. In origin, we factor analyzed the lifetime symptomatology of bipolar disorder, major depressive disorder, schizophrenia and delusional disorder. Major depressive disorder has been largely analyzed. Delusional subtype has been investigated and it resulted a more severe form of depressive disorder. A factor analysis of major depression allowed identifying its basic components that are depressive, delusional and atypical symptoms. Also for delusional disorder we reported the largest sample ever published with the identification of separate cluster of symptoms including depressed mood, hallucination, delusional and irritability items. Mania too was dissected in its basic components. Finally, we reported the largest sample of dysthymic patients ever studied, and factor analysis results indicate that dysthymic disorder appears to primarily involve psychologic symptoms, and only the most severe forms involve neurovegetative disturbances. Those findings have both diagnostic and therapeutic relevance. More recently, we studied clinical features of mood disorder subtypes and we evidenced specific features of bipolar disorder compared to major depressive disorder.


Genetic predictors of antidepressants response
A possible prediction of antidepressant response is of crucial importance in everyday practice. Up to now, few clinical features help for an early recognition of responders, however this is largely insufficient. Converging evidences suggest that genetic predisposition plays an important role in antidepressant response.
During last years we collected a sample of more than 600 subjects with major depression, including bipolars, with and without psychotic features and treated with fluvoxamine or paroxetine. We observed that the functional polymorphism in the upstream regulatory region of the serotonin transporter gene (SERTPR), was related to the antidepressant response to fluvoxamine. We replicated this finding with paroxetine 4 and sleep deprivation. The A218C gene variant on the tryptophan hydroxylase gene (TPH) and the G-protein beta3-subunit (Gbeta3) C825T gene variant were independently associated with SSRIs antidepressant efficacy. Short variants at the SERTPR have been associated with poor response in all studies performed in Caucasians, while in oriental populations results are conflicting. Variants on the Circadian Locomotor Output Cycles Kaput (CLOCK) gene were recently investigated in our center and showed a possible association with the time course of insomnia symptomatology.


Genetic predictors of lithium response
Lithium prophylactic efficacy in mood disorders is well known, but in clinical samples it ranges from complete prevention of affective episodes to no influence at all. Clinical predictors account for less than 50% of lithium prophylactic efficacy and it is probable that genetic factors play a substantial role. We investigated the possible association between the dopamine receptors D2, D3, D4, the serotonin receptors 2a, 2c, 1a, the upstream region of the serotonin transporter gene (5-HTTLPR), and the tryptophan hydroxylase (TPH) genes with the prophylactic efficacy of lithium in mood disorders.
DRD2, DRD3, DRD4, 5HT2a, 5HT2c, 5HT1a, COMT, MAO-A and Gbeta3 variants were not associated with lithium outcome, while 5-HTTLPR and TPH variants were associated with lithium outcome. We also reported that melancholic features are independently associated with lithium outcome. We may therefore provisionally hypothesize that part of the variance of the prophylactic efficacy of lithium may be regulated by the overall activity of the serotonergic system, with a possible complex interaction with symptomatology. The genetic prediction of lithium efficacy would be of great benefit for clinicians because a long time is needed in order to identify responders.


Influence of clock genes on circadian rythms in major psychoses
Recent observations about the role of the “clock” genes in regulating mammalian circadian rhythmicity raised interest about the possible involvement of a genetic mechanism in frequent circadian rhythms abnormalities, typical of major depressive episodes. We preliminarily, focused on a polymorphism (T to C nucleotide substitution) in the 3’ flanking region of the human CLOCK gene that seems to be associated with diurnal preferences of human healthy subjects, with higher “eveningness” in subjects carrying at least one copy of the C allele. We investigated its possible role in regulating diurnal mood fluctuations, during a major depressive episode; no significant difference was founded, but a higher recurrence rate in CC subjects. Since sleep disturbances are commonly observed in mood disorders, and sleep manipulations can influence the clinical status, we studied the possible effect of this polymorphism on insomnia symptomatology during antidepressant treatment. We observed a significantly higher presence of insomnia throughout the trial in CC subjects. Overall, our findings suggest that this CLOCK polymorphism influences the time course of insomnia, during antidepressant treatment; this fact, together with the previous finding, could lead to a further dissection of the complexity of Mood Disorders.


A genome wide mapping approach for mood disorders susceptibility loci, in a sib pairs sample
Despite the high number of genetics and pharmacogenetics findings, which demonstrated the hereditability of Major Psychoses, to date, only few genes have been clearly identified, as candidate. For this reason, detection of the genetic bases for mood disorders remains an important challenge for human health. Past linkage studies identified several susceptibility chromosomal regions. In recent times, we are performing a wide genome scan (cM 10), in Italian sib pairs, with, at least, one of the sibs by the couple, affected by mood disorders. Our very preliminary results, considering 35 sib pairs, showed an interesting susceptibility region (12q13-14) on Chromosome 12, which previously resulted, interestingly involved in affective disorders, by independent international studies. This finding is an important starting point, which prompt us to enlarge our sample and to carry on wide mapping on the whole human genome.

 

References

Serretti, A., Lattuada, E., Lorenzi, C., Lilli, R., and Smeraldi, E., 2000, Dopamine receptor D2 ser/cys 311 variant is associated with delusion and disorganization symptomatology in major psychoses, Molecular Psychiatry 5:270-274.


Zanardi, R., Artigas, F., Moresco, R., Colombo, C., Messa, C., Gobbo, C., Smeraldi, E., and Fazio, F., 2001, Increased 5-hydroxytryptamine-2 receptor binding in the frontal cortex of depressed patients responding to paroxetine treatment: a positron emission tomography scan study, J Clin Psychopharmacol 21(1): 53-8.


Serretti, A., Lorenzi, C., Lilli, R., Mandelli, L., Pirovano, A., and Smeraldi, E., 2002, Pharmacogenetics of lithium prophylaxis in mood disorders: Analysis of COMT, MAO-A, and Gbeta3 variants, Am J Med Genet 114(4): 370-379.
Serretti, A., Benedetti, F., Mandelli, L., Lorenzi, C., Pirovano, A., Colombo, C., and Smeraldi, E., 2003, Genetic dissection of psychopathological symptoms: Insomnia in mood disorders and CLOCK gene polymorphism, Am J Med Genet 121B(1): 39-43.


Serretti, A., Lorenzi, C., Cusin, C., Zanardi, R., Lattuada, E., Rossini, D., Lilli, R., Pirovano, A., Catalano, M., and Smeraldi, E., 2003, SSRIs antidepressant activity is influenced by Gbeta3 variants, Eur Neuropsychopharmacol 13(2): 117-22.


Benedetti, F., Colombo, C., Serretti, A., Lorenzi, C., Pontiggia, A., Barbini, B., and Smeraldi, E., 2003, Antidepressant effects of light therapy combined with sleep deprivation are influenced by a functional polymorphism within the promoter of the serotonin transporter gene, Biol Psychiatry 54(7): 687-92.


Benedetti, F., Serretti, A., Colombo, C., Barbini, B., Lorenzi, C., Campori, E., and Smeraldi, E., 2003, Influence of CLOCK gene polymorphism on circadian mood fluctuation and illness recurrence in bipolar depression, Am J Med Genet 123B(1): 23-6.


Lorenzi, C., Serretti, A., Mandelli, L., Tubazio, V., Ploia, C., and Smeraldi, E., 2005, 5-HT(1A) polymorphism and self-transcendence in mood disorders, Am J Med Genet B Neuropsychiatr Genet 10:10.


Serretti, A., Benedetti, F., Zanardi, R., and Smeraldi, E., 2005, The influence of Serotonin Transporter Promoter Polymorphism (SERTPR) and other polymorphisms of the serotonin pathway on the efficacy of antidepressant treatments, Prog Neuropsychopharmacol Biol Psychiatry.


Pirovano, A., Lorenzi, C., Serretti, A., Ploia, C., Landoni, S., Catalano, M., and Smeraldi, E.,  In press, Two new rare variants in the circadian "clock" gene may influence sleep pattern, Genetics in Medicine.