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Dysfunctional glutamatergic neurotransmission has been proposed both, as a biological underpinning of mood disorder and as a target for rapid-acting antidepressant treatments. Total sleep deprivation and light therapy (TSD + LT) can prompt antidepressant response in drug-resistant bipolar depression. Here we explored the effects of TSD + LT on dorsolateral prefrontal cortex (DLPFC) glutamate and/or glutamine+glutamate (Glx) levels.We studied single voxelHigher concentration of Glu (adjusted Z = -2189, p = 0,0285) and Glx (adjusted Z = -3,13, p = 0,0017) were observed in BD patients compared to HC. Treatment caused a significant rapid reduction of depressive symptom severity over time (F = 63.98, p 0.01). Change in depression levels after TSD + LT treatment was significantly influenced by delta change in Glu levels (LR χA reduction in Glu and Glx levels associated with depression could contribute to the mechanism of action of TSD + LT, directly acting on glutamatergic neurons, or to the interaction between the glutamatergic system and dopamine (DA) and serotonin (5-HT) levels, known to be targeted by TSD. This is in line with several studies showing a glutamatergic modulation effects of antidepressants and mood stabilizing agents. This finding deepens our understanding of antidepressant effect of chronoterapeutics.

The aim of this study is to objectively evaluate sleep architecture changes of depressed bipolar subjects treated with chronoterapeutics. Eleven depressed bipolar inpatients received 3 cycles of Total Sleep Deprivation, followed by daily light therapy sessions for one week. Polysomnography was performed before and after the treatment. Depressive symptoms significantly reduced, and sleep architecture changed with significant differences in N2% and N3% and REM density. Change in N3% was also positively correlated to depressive symptoms reduction. Although, previous studies reported sleep architecture changes after chronoterapeutics in unipolar depression, this is the first study to demonstrate changes also in bipolar depressed subjects.

Dysfunctional glutamatergic neurotransmission has been proposed both, as a biological underpinning of mood disorder and as a target for rapid-acting antidepressant treatments. Total sleep deprivation and light therapy (TSD+LT) can prompt antidepressant response in drug-resistant bipolar depression. Here we explored the effects of TSD+LT on dorsolateral prefrontal cortex (DLPFC) glutamate and/or glutamine+glutamate (Glx) levels.

Blue blocking glasses for the treatment of mania in an elderly patient: a case report with polysomnographic findings.

IntroductionSuicides that occur during psychiatric hospitalization are tragic events causing immense distress to relatives, peers, and physicians. Suicide risk is particularly high in patients with mood disorders.ObjectivesTo identify a clinical risk profile which can be predictive of suicide in patients undergoing a major depressive episode, hospitalized and within three months after discharge.MethodsWe are going to include consecutively admitted depressed patients in San Raffaele Turro hospital (Milan), with a diagnosis of major depressive disorder or bipolar disorder, for a longitudinal prospective study. Demographical and clinical characteristics will be assessed. Barratt impulsiveness scale, aggression questionnaire, Hamilton psychiatric rating scale for depression, scale for suicide ideation, Columbia suicide severity rating scale will be administered to evaluate, respectively, traits of impulsiveness and aggression, severity of psychopathology and suicidal ideation. A follow-up program has been established to evaluate suicidal ideation one month and three months after discharge.ResultsConsidering suicide rates in other psychiatric wards, we retrospectively analyzed in our mood disorder unit the inpatient suicide rate of the last 3 years. In this period, we admitted 1794 patients. The suicide rate has been cumulatively of 0.17% (4 patients): 0.16% in 2014, 0.16% in 2015, and 0.19% in 2016. In the same period, outpatient suicide rate has been of 0.39%; 57.14% of outpatient suicides happened within three months after discharge.ConclusionsHospitalization and discharge are critical circumstances for psychiatric patients. Evaluation of risk factors will contribute to explain our ward suicide rate and hopefully to reduce it in the future.Disclosure of interestThe authors have not supplied their declaration of competing interest.

The combination of total steep 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. The combination of total steep 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.

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. (c) 2007 Wiley-Liss, Inc. 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. (c) 2007 Wiley-Liss, Inc.

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. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.

Forty bipolar depressed inpatients underwent three consecutive cycles of total sleep deprivation (TSD). At the beginning of the study, 20 patients were free of psychotropic drugs and 20 had been receiving Lithium medication for at least 6 months. Mood was rated on the Hamilton Rating Scale for Depression before and after TSD; perceived mood changes during treatment were evaluated with self-administered visual analog scales. Patients undergoing long-term lithium treatment showed a significantly better response to TSD as rated on both scales: 13 of 30 patients (rs. 2 of 20 patients without Lithium) showed a sustained response during a follow-up period of 3 months. This preliminary evidence of a positive interaction of TSD and long-term Lithium treatment could be explained by a synergistic effect of both treatments on brain serotonergic function, possibly via a desensitization of 5-hydroxytryptamine-1A inhibitory autoreceptors.

Total sleep deprivation (TSD) shows powerful but transient clinical effects in patients affected by bipolar depression. Pindolol blocks the serotonergic 5-HT1A autoreceptor, thus improving the antidepressant effect of selective serotonin reuptake inhibitors. We evaluated the interaction of TSD and pindolol in the treatment of acute episodes of bipolar depression. Forty bipolar depressed inpatients were randomized to receive pindolol 7.5 mg/day or placebo for nine days in combination with three consecutive TSD cycles. Pindolol significantly improved the antidepressant effect of TSD, and prevented the short-term relapse after treatment. The response rate (HDRS scores

Fifty-one inpatients affected by a major depressive episode were divided into four groups according to mood disorder diagnosis and previous clinical history (bipolar disorder type I; bipolar disorder type II; major depressive disorder with at least three previous depressive episodes; and single depressive episode patients) and administered three consecutive total sleep deprivation (TSD) cycles. Mood changes were rated with a reduced version of the Hamilton Depression Rating Scale and with self-administered visual analogue scales. TSD caused better clinical effects in bipolar and single-episode patients; in particular, unipolar patients lacked effects in perceived mood after the first TSD and showed worse Hamilton ratings in respect to the other groups after the three TSD treatments. Discriminant function analysis could correctly classify 80% of bipolar patients, post hoc, based on TSD response. Further researches on the clinical efficacy of TSD must take into account the heterogeneity of depression and of its biological substrate. (C) 1998 Elsevier Science Ireland Ltd. All rights reserved.

IntroductionPatients affected by severe manic episode, often with delusional symptoms, are commonly treated with a combination of mood stabilizers, antipsychotics and other sedatives. The choice of a specific drug, dose and term is still debated.ObjectivesA naturalistic study on a sample of 84 inpatients affected by acute severe mania treated with a combination therapy.AimsTo compare efficacy and tolerability of haloperidol/risperidone/quetiapine in association with lithium and/or valproate.MethodsEighty-four bipolar inpatients affected by a manic episode according to DSM-5 criteria. Drugs administered according to our best practice. Clinical course weekly monitored with Young Mania Rating Scale (YMRS) for 4weeks. Extrapiramidal side effects (EPSE) monitored with Saint Hans Rating Scale (SHRS).ResultsTwenty-five men (29.76%) and 59 women (70.24%); mean age 43.37 ± 13.58 years. Mean YMRS score T0 40.27 ± 9.04. Forty-one patients (48.81%) treated with haloperidol (3.4 mg/die); 16 (19.05%) with risperidone (4.3 mg/die); 27 (32.14%) with quetiapine (438 mg/die). The 3 groups showed no difference regarding clinical characteristics and YMRS basal scores. Chi2 analysis confirmed an higher response rate (50% of reduction of YMRS final score compared to T0) with haloperidol (χ2 = 14.88; P = 0.00). The repeated-measures model analysis showed a significant decrease (P < 0.05) in YMRS scores in haloperidol vs. risperidone vs. quetiapine patients for all time points from second week. No statistical difference for EPSE was found.ConslusionsWe suggest that haloperidol could be advisable in the treatment of severe mania, with rapid efficacy, even with low doses. Occurrence of EPSE was not considerable during the acute treatment. Studies with a larger sample size, randomization, fixed doses, double blind design are needed.Disclosure of interestThe authors have not supplied their declaration of competing interest.

"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 patient's 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.. . "

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 ill 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. (C) 2009 Elsevier B.V. All rights reserved.

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. (c) 2008 Elsevier Inc. All rights reserved. 5-HT(2A) receptor density in prefrontal cortex was associated with depression and suicide.5-HT(2A) receptor gene polymorphism rs6313 was associated with 5-HT(2A) 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-HT(2A) 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. (c) 2008 Elsevier Inc. All rights reserved.

Psychiatric chronotherapeutics is the controlled exposure to environmental stimuli that act on biological rhythms in order to achieve therapeutic effects in the treatment of psychiatric conditions. In recent years some techniques (mainly light therapy and sleep deprivation) have passed the experimental developmental phase and reached the status of powerful and affordable clinical interventions for everyday clinical treatment of depressed patients. These techniques target the same brain neurotransmitter systems and the same brain areas as do antidepressant drugs, and should be administered under careful medical supervision. Their effects are rapid and transient, but can be stabilised by combining techniques among themselves or together with common drug treatments. Antidepressant chronotherapeutics target the broadly defined depressive syndrome, with response and relapse rates similar to those obtained with antidepressant drugs, and good results are obtained even in difficult-to-treat conditions such as bipolar depression. Chronotherapeutics offer a benign alternative to more radical treatments of depression for the treatment of severe depression in psychiatric wards, but with the advantage of rapidity of onset. (C) 2007 Elsevier Ltd. All rights reserved. Psychiatric chronotherapeutics is the controlled exposure to environmental stimuli that act on biological rhythms in order to achieve therapeutic effects in the treatment of psychiatric conditions. In recent years some techniques (mainly light therapy and sleep deprivation) have passed the experimental developmental phase and reached the status of powerful and affordable clinical interventions for everyday clinical treatment of depressed patients. These techniques target the same brain neurotransmitter systems and the same brain areas as do antidepressant drugs, and should be administered under careful medical supervision. Their effects are rapid and transient, but can be stabilised by combining techniques among themselves or together with common drug treatments. Antidepressant chronotherapeutics target the broadly defined depressive syndrome, with response and relapse rates similar to those obtained with antidepressant drugs, and good results are obtained even in difficult-to-treat conditions such as bipolar depression. Chronotherapeutics offer a benign alternative to more radical treatments of depression for the treatment of severe depression in psychiatric wards, but with the advantage of rapidity of onset. (C) 2007 Elsevier Ltd. All rights reserved.

Introduction Major depression affects 1.5%-19% general population. High use of healthcare services and increase in morbidity and mortality are common consequences. Despite of appropriate pharmacological treatment, 30-40% of patients don't achieve significant improvement. TRD refers to no remission after two adequate trials of antidepressants: these patients qualify for ECT. Objectives Our Mood Disorder Unit treats about 600 patients/year, 4% undergo ECT for TRD. Aim Ongoing, retrospective, observational study on 73 TRD patients treated with ECT 2/week, considering acute and late responsiveness 1 and 12 months later. Methods Sample of 52 (71.22%) patients with Recurrent Major Depression and 21 (28.78%) with Bipolar Disorder, collecting epidemiological and clinical data. Clinical course assessment through weekly Hamilton Rating Scale for Depression (HRSD); follow-up evaluation after 12 months, with telephone interviews. Results 73 inpatients, 26(35.62%) males, 47(64.38%) females with 4.31±3.43 previous episodes; mean age 59.42±11.60 years. Average duration of reference episode 52.71±39.42 weeks with HRSD initial score 30.16±4.76. Each patient was treated with 6.92±2.90 ECT applications. 64(87.67%) patients responded to treatment (50% reduction of HRSD initial score), 33(45.21%) achieved remission (HRSD≤8); 18(24.66%) patients maintained 12-months remission. Conclusion Our experience strengthens pivotal role of ECT in TRD. Each patient had long-lasting, severe episode under 1 year-long unsuccessful pharmacological therapy. ECT managed to quickly ameliorate their clinical course. We didn't record any adverse event. ECT showed similar relapse rates compared to conventional pharmacological treatment. This procedure requires further studies about long-term outcome.

Background: Drug resistance remains a persistent source of morbidity and mortality for patients with bipolar depression. A growing number of clinical studies support the usefulness of chronotherapeutic interventions, such as total sleep deprivation (TSD) and light therapy (LT), In the treatment of nonresistant bipolar depression. Method: To investigate the clinical usefulness of TSD plus LT in the treatment of drug-resistant bipolar depression, we treated 60 inpatients for I week with repeated TSD and LT combined with ongoing antidepressants and lithium salts. All patients had a DSM-IV diagnosis of bipolar I disorder. Drug resistance was rated according to Thase and Rush criteria. The pattern of relapses and recurrences was assessed during a prospective 9-month follow-up. Data were gathered from September 2002 to July 2004. Results: A 2-way repeated-measures analysis of variance with changes in self-rated perceived mood scores as dependent variable and with time and group (history of drug resistance) as independent factors confirmed significant time-by-group interaction (p = .0339). A logistic regression on rates of achievement of response (50% reduction in Hamilton Rating Scale for Depression ratings) confirmed the significance of observed differences: overall, 70% (23/33) of nonresistant versus 44% (12/27) of drug-resistant patients achieved response (p = .045). A survival time analysis (Cox proportional hazards model) showed that history of drug resistance significantly influenced the pattern of relapses and recurrences, with 57% (13/23) of nonresistant responders and 17% (2/12) of drug-resistant responders being euthymic after 9 months (p = .0212). Discussion: The combination of repeated TSD and LT in drug-resistant patients was useful in triggering an acute response. Further clinical research is needed to optimize this treatment option for drug-resistant patients in the long term. Background: Drug resistance remains a persistent source of morbidity and mortality for patients with bipolar depression. A growing number of clinical studies support the usefulness of chronotherapeutic interventions, such as total sleep deprivation (TSD) and light therapy (LT), In the treatment of nonresistant bipolar depression. Method: To investigate the clinical usefulness of TSD plus LT in the treatment of drug-resistant bipolar depression, we treated 60 inpatients for I week with repeated TSD and LT combined with ongoing antidepressants and lithium salts. All patients had a DSM-IV diagnosis of bipolar I disorder. Drug resistance was rated according to Thase and Rush criteria. The pattern of relapses and recurrences was assessed during a prospective 9-month follow-up. Data were gathered from September 2002 to July 2004. Results: A 2-way repeated-measures analysis of variance with changes in self-rated perceived mood scores as dependent variable and with time and group (history of drug resistance) as independent factors confirmed significant time-by-group interaction (p = .0339). A logistic regression on rates of achievement of response (50% reduction in Hamilton Rating Scale for Depression ratings) confirmed the significance of observed differences: overall, 70% (23/33) of nonresistant versus 44% (12/27) of drug-resistant patients achieved response (p = .045). A survival time analysis (Cox proportional hazards model) showed that history of drug resistance significantly influenced the pattern of relapses and recurrences, with 57% (13/23) of nonresistant responders and 17% (2/12) of drug-resistant responders being euthymic after 9 months (p = .0212). Discussion: The combination of repeated TSD and LT in drug-resistant patients was useful in triggering an acute response. Further clinical research is needed to optimize this treatment option for drug-resistant patients in the long term.

Background: Recent findings suggest that extended bed rest and darkness could stabilize mood swings in rapid cycling bipolar patients. Method: We exposed 16 bipolar inpatients affected by a manic episode to a regimen of 14 h of enforced darkness from 6 p.m. to 8 a.m. each night for three consecutive days [dark therapy (DT)]. Pattern of mood changes were recorded with the Young Mania Rating Scale (YMRS) and compared with a control group of 16 inpatients matched for age, sex, age at onset, number of previous illness episodes and duration of current episode, and were treated with therapy as usual (TAU). Results: Adding DT to TAU resulted in a significantly faster decrease of YMRS scores when patients were treated within 2 weeks from the onset of the current manic episode. When duration of current episode was longer, DT had no effect. Follow-up confirmed that good responders needed a lower dose of antimanic drugs and were discharged earlier from the hospital. Conclusions: Chronobiological interventions and control of environmental stimuli can be a useful add-on for the treatment of acute mania in a hospital setting. Background: Recent findings suggest that extended bed rest and darkness could stabilize mood swings in rapid cycling bipolar patients. Method: We exposed 16 bipolar inpatients affected by a manic episode to a regimen of 14 h of enforced darkness from 6 p.m. to 8 a.m. each night for three consecutive days [dark therapy (DT)]. Pattern of mood changes were recorded with the Young Mania Rating Scale (YMRS) and compared with a control group of 16 inpatients matched for age, sex, age at onset, number of previous illness episodes and duration of current episode, and were treated with therapy as usual (TAU). Results: Adding DT to TAU resulted in a significantly faster decrease of YMRS scores when patients were treated within 2 weeks from the onset of the current manic episode. When duration of current episode was longer, DT had no effect. Follow-up confirmed that good responders needed a lower dose of antimanic drugs and were discharged earlier from the hospital. Conclusions: Chronobiological interventions and control of environmental stimuli can be a useful add-on for the treatment of acute mania in a hospital setting.

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. (C) 2003 Society of Biological Psychiatry.

Background: Bright artificial light improves non-seasonal depression. Preliminary observations suggest that sunlight could share this effect. Methods: Length of hospitalization was recorded for a sample of 415 unipolar and 187 bipolar depressed inpatients, assigned to rooms with eastern (E) or western (W) windows, Results: Bipolar inpatients in E rooms (exposed to direct sunlight in the morning) had a mean 3.67-day shorter hospital stay than patients in W rooms. No effect was found in unipolar inpatients. Conclusions: Natural sunlight can be an underestimated and uncontrolled light therapy for bipolar depression. Limitations: This is a naturalistic retrospective observation, which needs to be confirmed by prospective studies. (C) 2001 Elsevier Science B.V. All rights reserved.

The clinical usefulness of total sleep deprivation (TSD) in the treatment of bipolar depression is hampered by a high-rate short-term relapse. Previous literature has suggested that both long-term lithium treatment and light therapy could successfully prevent relapse. We randomized 115 bipolar depressed inpatients to receive three cycles of TSD, alone or in combination with morning light exposure, given at an intensity of 150 or 2500 lux. Forty-nine patients were undergoing long-term treatment with lithium salts (at least 6 months), while 66 patients were taking no psychotropic medication. Mood was self-rated by the Visual Analogue Scale three times a day during treatment. The results showed that both light therapy and ongoing lithium treatment significantly enhanced the effects of TSD on the perceived mood, with no additional benefit when the two treatments were combined. Subjective sleepiness during TSD, as rated by the self-administered Stanford Sleepiness Scale, was significantly reduced by light exposure, and was correlated with the outcome. This study confirms the possibility of obtaining a sustained antidepressant response to TSD in bipolar patients. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved.

Objective: A functional polymorphism in the transcriptional control region upstream of the coding sequence of the 5-hydroxytryptamine transporter (5-HTT) has been reported. This polymorphism has been shown to influence the antidepressant response to fluvoxamine and paroxetine. The authors tested the hypothesis that the allelic variation of the 5-HTTlinked polymorphic region (5-HTTLPR) could influence the response of depressed patients to total sleep deprivation. Method: Sixty-eight drug-free inpatients with bipolar depression underwent a night of total sleep deprivation. 5-HTTLPR was genotyped in these patients. Changes in perceived mood were rated on a visual analogue scale and analyzed by using repeated measures analysis of covariance. Results: Patients who were homozygotic for the long variant of 5-HTTLPR showed a significantly better mood amelioration after total sleep deprivation than those who were heterozygotic and homozygotic for the short variant. Conclusions: The influence of 5-HTTLPR on response to total sleep deprivation is similar to its observed influence on response to serotonergic drug treatments. This finding supports the hypothesis of a major role for serotonin in the mechanism of action of total sleep deprivation in depression. (Am J Psychiatry 1999; 156:1450‐1452) The mechanism of action of total sleep deprivation in depression is still unclear. Total sleep deprivation enhances the functioning of several neurotransmitter systems, including brain serotonin (5-HT) pathways (1). The observation of a synergistic clinical effect between total sleep deprivation and the β adrenoreceptor/5HT1A antagonist pindolol, similar to that observed with pindolol and serotonergic drugs, supports a role for brain 5-HT in the mechanism of action of total sleep deprivation (2). A functional polymorphism in the transcriptional control region upstream of the coding sequence of the serotonin transporter (5-HTT) has been reported, and in vitro studies showed that the basal transcriptional activity of the long variant of this 5-HTT-linked polymorphic region (5-HTTLPR) was more than twice that of the short form (3). In agreement with these findings, a study in postmortem human brain tissue showed that subjects who were homozygotic for the long variant had higher 5-HTT mRNA levels than those who were heterozygotic and those who were homozygotic for the short variant (4). Moreover, in families with obsessivecompulsive disorder, subjects who were homozygotic for the long variant and heterozygotic had higher blood 5-HT levels than subjects who were homozygotic for the short variant (5). From a clinical perspective, 5-HTTLPR has been shown to influence the individual response to serotonergic drugs: depressed inpatients who were homozygotic for the long variant and heterozygotic had a better response to both fluvoxamine (6) and paroxetine (7) than those who were homozygotic for the short variant. If 5-HTTLPR has a clinically relevant influence on 5HT function, and if total sleep deprivation acts by enhancing 5-HT transmission, it can be hypothesized that 5-HTTLPR may be associated with different ef

Sleep deprivation is a potentially useful non-pharmacological treatment for depression. A relationship between sleep loss and the onset of mania has been reported, so it is possible that a switch from depression into mania after sleep deprivation might be expected in bipolar depressed patients who are treated with sleep deprivation. In a sample of 206 bipolar depressed treated with three cycles of sleep deprivation, alone or in combination with heterogeneous medications, we observed a 4.85% switch rate into mania and a 5.83% switch rate into hypomania. These percentages are comparable to those observed with antidepressant drug treatments. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved.

The purpose of the present study was to compare the efficacy of clozapine with that of chlorpromazine in an open label manner (both given in association with lithium salts) in the treatment of acute mania. Thirty hospitalized manic patients were entered into the study. All patients met DSM-IV criteria for bipolar disorder, Manic Episode; 27 patients completed the study and three patients dropped for noncompliance. The duration of the study was 3 weeks. Patients were randomly assigned to two treatment groups; group 1 (n = 15) was treated with clozapine at a mean dose of 166 mg/day and group 2 (n = 12) was treated with chlorpromazine at a mean dose of 310 mg/day. Manic symptomatology was rated on Young Rating Scale for Mania (YRSM) each week; side effects were recorded on dosage records and treatment emergent symptoms; extrapyramidal acute side effects were rated on the Simpson-Angus Rating Scale performed at the beginning of the study and after 3 weeks of treatment. A two-way repeated measures analysis of variance on YRMS scores showed a significant time effect (p < 0.0001) and a significant time-group interaction (p < 0.0001). Post-hoc comparison between the two groups showed a significant difference after 2 weeks of treatment (p = 0.0001), with clozapine treated patients showing lower YRSM scores than chlorpromazine treated patients. YRSM scores at the end of the study n;ere not significantly different. Patients treated with clozapine showed a more rapid trend toward amelioration. No clinically relevant side effect was observed during the study.

Among ten bipolar depressed patients admitted to our psychiatric ward, five patients were treated with fluoxetine alone and five subjects were treated with fluoxetine in association with total sleep deprivation (TSD) in order to evaluate the effect of the interaction between the administration of the serotonergic antidepressant compound fluoxetine and repeated cycles of TSD. Patients treated with fluoxetine plus repeated TSD showed a faster amelioration of depressive symptomatology compared with the other group. We discuss our findings hypothesizing an enhancement in dopaminergic and possibly in serotonergic transmission due to repeated TSD adding to the increase in serotonergic transmission due to fluoxetine medication.

In a double-blind study, the effects of the interaction between the administration of amineptine versus placebo and repeated cycles of total sleep deprivation (TSD), which is thought to act through an enhancement in dopaminergic transmission, were analyzed. Twenty-two consecutively admitted patients with bipolar depression formed the study group. Repeated administrations of TSD significantly enhanced perceived mood levels in placebo-treated patients, while amineptine administration blocked the antidepressant action of TSD. Hypothesized changes in brain dopaminergic transmission attributable to amineptine pretreatment are discussed. Copyright (C) 1996 Elsevier Science Ireland Ltd.

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.

Several reports suggest the role of sleep-wake rhythm in mood disorders. Sleep loss may be a possible trigger or augmenting factor in mania. In a group of 34 manic bipolar inpatients, we analyzed the correlation between night-time sleep duration and the intensity of manic symptomatology rated consecutively for 3 days with the Young Rating Scale for Mania and the Nurses' Observation Scale for Inpatient Evaluation (NOSIE). We found significant correlations between sleep duration and NOSIE cluster scores (cooperation and irritability). Copyright (C) 1996 Elsevier Science Ireland Ltd.

SummaryThe aim of the present study is to evaluate the seasonal pattern of recurrences and the concordance among first episode (index episode) versus the subsequent recurrences in a sample of 210 patients affected by mood disorders, referred to the Mood Disorder Unit of San Raffaele Hospital. The most depressive recurrences are in spring for unipolar subjects and in fall for bipolars. Manic episodes are more frequent in summer. Patients presented a high concordance rate between the first and the second episode, female patients were more concordant than male subjects, and patients with low cycle of illness (one episode every six or more years) were the most concordant ones.

Recent studies showed that a polymorphism (T to C nucleotide substitution) in the 3' flanking region of the human CLOCK gene is associated with diurnal preferences of human healthy subjects, with higher "eveningness" in subjects carrying at least one copy of the C allele. We investigated the possible role of CLOCK gene polymorphism in the regulation of diurnal mood fluctuations during a major depressive episode. Sample (n = 101) was collected, in the context of previously reported trials, among patients affected by bipolar disorder type 1, depressive episode without psychotic features, free of psychotropic medications. Perceived mood levels were assessed three times a day with self-administered visual analogue scales. Genotype groups showed no significant difference in diurnal mood fluctuations. When stratifying the sample by including only patients with an adequate period of observation (duration of illness higher than 5 years, n = 69), we post-hoc observed a significantly higher recurrence rate in homozygotes for the C variant, which was almost double than that of the other genotype groups. This preliminary observation leads to hypothesize a role for the CLOCK gene polymorphism in the regulation of long-term illness recurrence in bipolar disorder. Given the post-hoc nature of the finding, replication in independent samples is necessary to confirm it. (C) 2003 Wiley-Liss, Inc.