Adriana Pontiggia

Long-term response to lithium salts in bipolar illness is influenced by the glycogen synthase kinase 3-β-50 T/C SNP

The molecular mechanisms driving the biological clock in the suprachiasmatic nucleus of the hypothalamus may play a role in mood disorders. A single nucleotide polymorphism (SNP) (-50 T/C) falling into the effective promoter region (nt -171 to +29) of the gene coding for glycogen synthase kinase 3-beta (GSK3-beta) has been linked with different age at onset of bipolar illness and with different antidepressant effects of total sleep deprivation. GSK3-beta codes for an enzyme which is a target for the action of lithium and possibly of valproic acid. We studied the effect of this polymorphism on the therapeutic response to lithium salts of 88 bipolar type I patients. Data about recurrence rate of mood episodes were collected for at least 2 years before lithium and 2 years on lithium. Results showed that homozygotes for the wild variant did not change their recurrence index while carriers of the mutant allele improved, thus supporting the hypothesis that GSK is a target for the therapeutic action of lithium. Results warrant interest for the variants of genes pertaining to the molecular clock as possible endophenotypes of bipolar disorder, but caution ought to be taken in interpreting these preliminary results and future replication studies must be awaited because of the low frequency of the GSK3-beta*C/C genotype in the studied populations.

A single nucleotide polymorphism in glycogen synthase kinase 3-β promoter gene influences onset of illness in patients affected by bipolar disorder

Genetic studies in medicine exploited age of onset as a criterion to delineate subgroups of illness. Bipolar patients stratified with this criterion were shown to share clinical characteristics and patterns of inheritance of illness. The molecular mechanisms driving the biological clock in the suprachiasmatic nucleus of the hypothalamus may play a role in mood disorders. A single nucleotide polymorphism (SNP) (-50 T/C) falling into the effective promoter region (nt -171 to +29) of the gene coding for glycogen synthase kinase 3-beta (GSK3-beta) has been identified. GSK3-beta codes for an enzyme which is a target for the action of lithium and which is also known to regulate circadian rhythms in Drosophila. We studied the effect of this polymorphism on the age at onset of bipolar disorder type I. A homogeneous sample of 185 Italian patients affected by bipolar disorder was genotyped. Age at onset was retrospectively ascertained with best estimation procedures. No association was detected between GSK3-beta -50 T/C SNP and the presence of bipolar illness. Homozygotes for the wild variant (T/T) showed an earlier age at onset than carriers of the mutant allele (F=5.53, d.f.=2,182, P=0.0047). Results warrant interest for the variants of genes pertaining to the molecular clock as possible endophenotypes of bipolar disorder, but caution ought to be taken in interpreting these preliminary results and future replication studies must be awaited.

Antidepressant effects of light therapy combined with sleep deprivation are influenced by a functional polymorphism within the promoter of the serotonin transporter gene

BACKGROUND A functional polymorphism within the promoter of the serotonin transporter has been shown to influence the antidepressant response to serotonergic drug treatments and to total sleep deprivation (TSD). The short-term relapse that follows acute response to TSD has been successfully prevented by combining TSD with light therapy. The mechanism of action of this combined treatment is unknown. METHODS We tested the hypothesis that allelic variation of the serotonin transporter (5-HTT) linked polymorphic region (5-HTTLPR) could influence the response to the combination of light therapy and TSD. Twenty-two bipolar depressed inpatients were administered a night of TSD combined with 30 min light therapy given during the TSD night and in the morning after recovery sleep. 5-HTTLPR was genotyped using polymerase chain reaction techniques. Changes in perceived mood were rated on a visual analog scale. RESULTS Light therapy sustained the effect of TSD. The effect was more marked in homozygotes for the long variant of 5-HTTLPR than in heterozygotes and homozygotes for the short variant. CONCLUSIONS The influence of 5-HTTLPR on response to the combination of TSD and light therapy is similar to that observed on response to TSD and serotonergic drug treatments.

Sleep phase advance and lithium to sustain the antidepressant effect of total sleep deprivation in bipolar depression: new findings supporting the internal coincidence model?

Recent European studies suggested that sleep phase advance (SPA) could sustain the effects of total sleep deprivation (TSD) both with or without a combined antidepressant drug treatment. Previous studies by our group showed that an ongoing lithium treatment could enhance and sustain the effect of repeated TSD. In the present study we studied the effect of a single TSD followed by 3 days SPA (beginning with sleep allowed from 17:00 until 24:00, with daily shiftbacks of 2 h) in consecutively admitted bipolar depressed inpatients who were taking a chronic lithium salts treatment (n=16) or who were devoid of psychotropic medications (n=14). Changes in mood during treatment were recorded with self administered visual analogue scales and with Hamilton rating scale for depression. Results showed that SPA could sustain the acute antidepressant effect of TSD, and that lithium enhanced the effect of the chronobiological treatment. According to the internal coincidence model, the better clinical effects observed in lithium-treated patients could be due to the phase delaying effect of lithium on biological rhythms, leading to a better synchronization of biological rhythms with the sleep-wake cycle.

Depression and neurological disorders.

Purpose of review Clinical studies support a bidirectional link between depression and neurological diseases. Here we review the most recent findings supporting the hypothesis that major depression is a medical illness of the brain which can be elicited by neurological illnesses. Recent findings In the last year major improvements in brain-imaging techniques allowed correlations to be demonstrated between functional and structural brain abnormalities in specific brain areas (prefrontal cortex, hippocampus, cingulate gyrus) and the presence and severity of affective disorders, thus suggesting a neural basis for their onset and progression. Similar lesions, caused by neurological diseases, have been found to correlate with the presence of depression in neurological illnesses, but literature on the topic is still lacking. Depression in neurological disorders responds to the same treatments available for idiopathic major depression, but patients seem to have different sensitivities to side effects depending on their specific neurological syndrome. Most available data come from case reports and open trials. Summary ‘Psychiatric’ and ‘neurologic’ depression seem to share common abnormalities in specific brain areas, but sound brain-imaging studies of the neural correlates of depression in neurological disorders are still lacking. Available treatments are efficacious, but no clear-cut guidelines about the best drugs and dosages can be defined because double-blind placebo-controlled studies are still scarce.

New perspectives on techniques for the clinical psychiatrist: Brain stimulation, chronobiology and psychiatric brain imaging

This review summarizes a scientific dialogue between representatives in non‐pharmacological treatment options of affective disorders. Among the recently introduced somatic treatments for depression those with most evidenced efficacy will be discussed. The first part of this article presents current opinions about the clinical applications of transcranial magnetic stimulation in the treatment of depression. The second part explains the most relevant uses of chronobiology in mood disorders, while the last part deals with the main perspectives on brain imaging techniques in psychiatry. The aim was to bridge gaps between the research evidence and clinical decisions, and reach an agreement on several key points of chronobiological and brain stimulation techniques, as well as on relevant objectives for future research.