Mara Cigala Fulgosi

Actimetric evidence that CLOCK 3111 T/C SNP influences sleep and activity patterns in patients affected by bipolar depression.

Depressive insomnia and diurnal fluctuations of mood and activity are core clinical features of mood disorders. Here we studied the effect of CLOCK 3111 T/C SNP (rs1801260) on the actimetric recorded diurnal activity and nocturnal sleep of 39 bipolar depressed inpatients. Compared to T/T homozygotes, carriers of the C allele had a similar degree of severity of depression, but showed higher activity levels in the evening, a delayed sleep onset (mean 79 min later), and a reduced amount of sleep during the night (mean 75 min less). Ongoing lithium treatment significantly interacted with rs1801260 by enhancing activity levels in the evening and reducing the differences among genotype groups. Individual characteristics of the molecular clock can influence sleep symptoms in mood disorders.

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.

Phase advance is an actimetric correlate of antidepressant response to sleep deprivation and light therapy in bipolar depression.

The combination of total sleep deprivation (TSD) and light therapy (LT) in bipolar depression causes rapid antidepressant effects, and its mechanism of action has been hypothesized to involve the enhancement of all of the monoaminergic systems targeted by antidepressant drugs (serotonin, dopamine, norepinephrine). It is still unknown if the clinical effects are paralleled by changes in biological rhythms. In a before/after design of a study of biological correlates of response, 39 inpatients affected by Type I Bipolar Disorder whose current depressive episode was without psychotic features were treated for one week with repeated TSD combined with morning LT. Wrist actigraphy was recorded throughout the study. Two‐thirds of the patients responded to treatment (50% reduction in Hamilton Depression score). Responders showed an increase in daytime activity, phase‐advance of the activity‐rest rhythm of 57 min compared to the pre‐treatment baseline, and reduced nighttime sleep. Non‐responders did not show significant changes in the parameters of their activity‐rest rhythm. Phase advance of the activity‐rest rhythm is an actimetric correlate of the antidepressant response to TSD and LT in bipolar depression. Results are consistent with the known effects of sleep‐wake manipulations and neurotransmitter function on the suprachiasmatic nucleus.

Dopaminergic augmentation of sleep deprivation effects in bipolar depression

Total sleep deprivation (TSD) has been used in association with lithium salts and with serotonergic and noradrenergic antidepressants, leading to sustained improvements in patients affected by major depression. Current theories on the neurobiological mechanism of action of TSD propose a major role for enhanced dopamine activity. To test the clinical relevance of dopaminergic enhancement in TSD, we treated a homogeneous sample of 28 bipolar depressed patients with three cycles of TSD combined with placebo or with the dopaminergic antidepressant amineptine. Changes in mood over time were rated with self-administered visual analogue scales and with the Montgomery-Asberg Depression Rating Scale. Patients showed improved mean daily-mood scores after TSD, an effect that was highest at the first cycle and decreased with treatment repetition. Amineptine enhanced the effects of TSD on perceived mood during the first two TSD cycles, but patients in the placebo and amineptine groups showed comparable results at the end of the treatment. Despite its theoretical importance, the clinical usefulness of combining TSD with a dopaminergic agent must be questioned.

Acute antidepressant response to sleep deprivation combined with light therapy is influenced by the catechol-O-methyltransferase Val(108/158)Met polymorphism

Catechol-O-methyltransferase (COMT) inactivates norepinephrine and dopamine via methyl conjugation, and a G-A transition in the COMT gene (rs4680) influences the enzyme activity. It is a current area of debate whether rs4680 can influence antidepressant response in major depressive disorder, and whether this influence extends to bipolar depression. Chronotherapeutic interventions, such as sleep deprivation and light therapy, are multi-target in nature and are effective in bipolar depression. Here we studied the effect of rs4680 on response to sleep deprivation combined with light therapy (36 h awake followed by a night of undisturbed sleep, with 10,000 lx light administered for 30 min during the night awake and upon awakening) in 87 bipolar depressed inpatients. Patients who were homozygotic for the Val/Val variant showed a significantly less efficient antidepressant effect after the night awake than those who were heterozygotic and homozygotic for the Met variant. This effect of rs4680 is similar to its observed influence on response to serotonergic and noradrenergic drug treatments in major depressive disorder. This is the first study reporting an influence of rs4680 on antidepressant response in bipolar depression. This finding supports the hypothesis of a major role for catecholamines in the mechanism of action of chronotherapeutics, and for rs4680 in modulating this effect.

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.

Seasonality and sleep: a clinical study on euthymic mood disorder patients.

Background. Research on mood disorders has progressively focused on the study of seasons and on the mood in association with them during depressive or manic episodes yet few studies have focused on the seasonal fluctuation that characterizes the patients clinical course both during an illness episode and during euthymic periods. Methods. 113 euthymic outpatients 46 affected by major recurrent depression and 67 affected by bipolar disorder were recruited. We evaluated the impact of clinical “rhythmical” factors: seasonality, sleep disturbance, and chronotype. Patients completed the SPAQ+ questionnaire, the MEQ questionnaire, and the medical outcomes study (MOS) sleep scale. We used t-test analyses to compare differences of clinical “rhythmical” and sociodemographic variables and of differences in the assessment scales among the diagnostic groups. Results. Patients reporting a family history for mood disorders have higher fluctuations throughout seasons. Sleep disturbance is more problematic in unipolars when compared to bipolars. Conclusions. Sleep, light, and seasonality seem to be three interconnected features that lie at the basis of chronobiology that, when altered, have an important effect both on the psychopathology and on the treatment of mood disorders.

Optimized light therapy for non-seasonal major depressive disorder: Effects of timing and season

BACKGROUND Light Therapy (LT) when combined with standard antidepressant treatment for unipolar depression hastens recovery. We studied the influence of LT timing on the antidepressant efficacy of LT and the influence of the season of treatment and recurrence on the response to treatment. METHODS We studied 70 inpatients affected by Unipolar Depression, treated for three weeks with combined LT and venlafaxine. Two-third of the patients received LT following a predictive algorithm based on MEQ scores; the others received LT at 11:00 a.m. Severity of depression was rated on the Hamilton Depression Rating Scale (HDRS). A subgroup of patients wore activity monitors. RESULTS HDRS scores significantly decreased during treatment (Friedmans ANOVA: χ2=186.82, p<0.00001). LT administered in the early morning showed a better relative efficacy than late morning (F=4.576; p=0.012) with the clinical improvement correlating with an advance in rest-activity rhythm acrophase (r=-0.336; p=0.017). Season of hospitalization interacted with LT timing and time in influencing response to treatment (F=3.101; p=0.049) and season of episode recurrence significantly interacted with LT timing, season of hospitalization and time (F=5.925; p=0.0035). LIMITATIONS The major limitation of the study is the small sample size when considering simultaneously LT schedules, season of treatment and recurrence. Moreover, even if none of the patients fulfilled DSM-IV criteria for seasonal pattern of recurrence, they were not administered any questionnaire about seasonality. CONCLUSIONS We confirmed the usefulness of LT as a non-pharmacological antidepressant therapy for non-seasonal depression. Season and timing of administration and timing of the rest-activity cycle affected response to treatment.

Paroxetine drops versus paroxetine tablets: Evaluation of compliance in a six-month study

AIMS Literature data show that one third of patients discontinue antidepressant therapy within the first month of treatment. The aim of this study was to evaluate whether paroxetine liquid solution 10 mg/ml may influence adherence inpatients receiving long-term treatment. METHODS 71 subjects affected by mood disorders or panic disorder were monitored for six months. The study sample was divided into two groups: controls (n=33) maintained their own therapy with paroxetine tablets; 38 patients maintained the same dosage of paroxetine, but shifted to liquid formulation 10 mg/ml. Compliance and general wellness were evaluated with the Medication Adherence Rating Scale (MARS) and the World Health Organization Quality of Life questionnaire (WhoQol). Data were analyzed using analysis of variance (ANOVA) and multivariate analysis of covariance (MANCOVA). RESULTS Significant differences were found in MARS scores: patients on oral solution 10 mg/ml showed an improvement of compliance month by month. In addition, age, formulation and quality of life had a significant impacton patient compliance. Significant correlations were found between MARS and quality of life. A specific paroxetine formulation could be a variable able to influence adherence to psychopharmacological treatment. The same consideration can be made for quality of life, sex and age that showed a trend towards improved adherence when compared with controls. Inparticular, the WhoQol subscale analysis of delta scores showed a significant difference in self-perception of quality of life inpatients treated with paroxetine either in tablet or drop formulation. DISCUSSION Formulation in drops 10 mg/ml is equally effective to tablets, but it may allow patients having a higher cognition and control on drug assumption.