Omega-3 polyunsaturated fatty acids in the prevention of relapse in patients with stable bipolar disorder: A 6-month pilot randomized controlled trial.

This study investigated the efficacy and safety of omega-3 polyunsaturated fatty acids (n-3 PUFAs) in relapse prevention of bipolar disorder (BD), addressing the shortcomings of current medications. Thirty-one stable BD patients were randomized to receive n-3 PUFAs or placebo for 6 months and intergroup differences in the incidence of the recurrence of bipolar depression were assessed. Differences in depression severity, manic symptoms, and routine biochemical parameters were also assessed. Interestingly, n-3 PUFAs demonstrated a favorable preventive effect on bipolar depression recurrence (p=0.005; Log-Rank) and reduced depression severity compared to placebo, and were well-tolerated, suggesting their potential as a safe prophylactic therapy for BD.

Illuminating the way: the role of bright light therapy in the treatment of depression.

INTRODUCTION: Despite the growing number of different therapeutic options, treatment of depression is still a challenge. A broader perspective reveals the benefits of bright light therapy (BLT). It stimulates intrinsically photosensitive retinal ganglion cells, which induces a complex cascade of events, including alterations in melatonergic, neurotrophic, GABAergic, glutamatergic, noradrenergic, serotonergic systems, and HPA axis, suggesting that BLT effects expand beyond the circadian pacemaker. AREAS COVERED: In this review, the authors present and discuss recent data of BLT in major depressive disorder, non-seasonal depression, bipolar depression or depressive phase of bipolar disorder, and seasonal affective disorder, as well as in treatment-resistant depression (TRD). The authors further highlight BLT effects in various depressive disorders compared to placebo and report data from several studies suggesting a response to BLT in TRD. Also, the authors report data showing that BLT can be used both as a monotherapy or in combination with other pharmacological treatments. EXPERT OPINION: BLT is an easy-to-use and low-budget therapy with good tolerability. Future studies should focus on clinical and biological predictors of response to BLT, on defining specific populations which may benefit from BLT and establishing treatment protocols regarding timing, frequency, and duration of BLT.

The effect of bright light therapy on irritability in bipolar depression: a single-blind randomised control trial.

OBJECTIVE: The symptom-complex irritability, widely used in descriptions of bipolar patients' manic and mixed states, also represents a common feature in depressive phases. Irritability negatively affects the clinical course of depression, leading to a higher risk of treatment non-adherence, violence, and suicide attempts. Nevertheless, proportional attention from the scientific literature seems to be scarce. We conducted the first randomised controlled trial with the aim of evaluating BLT as a possible therapeutic strategy for irritability in bipolar depression. METHODS: 180 inpatients were randomly assigned to: Group A exposed to bright light therapy (BLT) daily, or Group B treated with pharmacotherapy only. A qualitative assessment of irritability was performed after a 4-week program. RESULTS: Group A showed about one-third fewer cases of irritability compared to Group B, this reduction was not related to the overall remission of depressive symptoms. CONCLUSIONS: The present study supports the usefulness of BLT in irritability in bipolar depression.

Irritability is an underestimated feature of bipolar depression.Irritability is related to higher suicide risk and lower quality of life.Bright light therapy is an effective strategy to reduce irritability in bipolar depression.

Arketamine for bipolar depression: Open-label, dose-escalation, pilot study.

There are significantly fewer options for the treatment of bipolar depression than major depressive disorder, with an urgent need for alternative therapies. In this pilot study, we treated six subjects with bipolar disorder types I and II (according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria) who had been in a current depressive episode for at least four weeks. Four subjects were female (66.66%), and the mean age was 45.33 (±12.32). Subjects received adjunct treatment with two arketamine intravenous infusions one week apart-0.5 mg/kg first and then 1 mg/kg. The mean baseline Montgomery-Åsberg Depression Rating Scale (MADRS) total score was 36.66, which decreased to 27.83 24h after the first infusion of 0.5 mg/kg of arketamine (p = 0.036). In respect of the 1 mg/kg dose, the mean MADRS total score before the second infusion was 32.0, which dropped to 17.66 after 24h (p < 0.001). Arketamine appears to have rapid-acting antidepressant properties, consistent with previous animal studies on major depression. All individuals tolerated both doses, exhibiting nearly absent dissociation, and no manic symptoms. To the best of our knowledge, this pilot trial is the first to test the feasibility and safety of the (R)-enantiomer of ketamine (arketamine) for bipolar depression.

Effectiveness of light therapy as adjunctive treatment in bipolar depression: A pilot study.

BACKGROUND: About 1 and 4 % of people suffering from depression is affected by bipolar disorder. Few patients respond to the first-line antidepressants, and a 4-week latency pharmacological treatment period has been observed. This pilot study aimed to evaluate the effectiveness and safety of bright light therapy (BLT) in accelerating and increasing therapeutic response in patients with bipolar depression. METHODS: A pilot study was conducted. Patients with bipolar depression, already treated with antidepressants, were included. The treatment group was composed of patients treated with antidepressants combined with BLT (30 min/4 days a week at 10,000 lx for eight weeks). The control group included patients treated with antidepressants with exposure to red light (30 min/4 days a week at a red light for eight weeks). MADRS, HAMD-17, CGI-S, FSS, and QoLS were collected at the baseline and after 4 and 8 weeks of treatments. RESULTS: Forty-one patients (18 males and 23 females; mean age 49.1 ± 15 years) were included in the study. After four weeks, MADRS and HAMD-17 scores in treatment groups were significantly lower than those reported in the control group (p < 0.001). After eight weeks, all scales except FSS reported significantly lower values in patients treated with BLT (p < 0.0001). LIMITATIONS: Small sample size and significant heterogeneity in the antidepressant treatments. CONCLUSION: BLT has shown reliable effectiveness and safety in treating patients with bipolar depression and should be considered a clinically relevant approach in accelerating patients' therapeutic response and reducing the impact of long-lasting therapy.

Alterations in CRY2 and PER3 gene expression associated with thalamic-limbic community structural abnormalities in patients with bipolar depression or unipolar depression.

Objectives The current study aimed to identify shared and distinct brain structure abnormalities and their relationships with the expression of circadian genes in patients with bipolar or unipolar depression. Method A total of 93 subjects participated in this study, including 32 patients with bipolar depression (BDP), 26 patients with unipolar depression (UDP) and 35 age- and sex-matched healthy controls. Brain structural magnetic resonance imaging scans were obtained, and optimized voxel-based morphometry was used to explore group differences in regional gray matter volume (GMV). The mRNA expression levels of circadian genes in peripheral blood were measured using reverse transcription quantitative real-time polymerase chain reaction. Results Our results showed that the GMV in brain regions in the thalamus-limbic pathways had significantly increased in the BDP patients compared to controls, while the increased GMV in UDP patients compared to controls was limited to the thalamus. The mRNA expression levels of circadian-related genes decreased significantly in patients with BDP, but increased in patients with UDP, compared to controls. In addition, the GMV in the right thalamus in the patients with UDP was positively associated with mRNA levels of CRY2, while the GMV in the right hippocampus in the patients with BDP was negatively associated with mRNA levels of PER3. Conclusion Our study suggested that patients with BDP or MDD shared GMV abnormalities in the right thalamus. The PER3 and CRY2 genes might be critical to right hippocampal dysfunction in BDP and right thalamic dysfunction in UDP, respectively. The result provided potentially important molecular targets for the treatment of mood disorders.

[Clinical characteristics and treatment of treatment-resistant bipolar depression].

Depression represents the predominant mood pole in bipolar disorder. Bipolar depression typically has a poor response to antidepressant medication, and also involves the risk of polarity shifts, induction of mixed states, and / or rapid cycle induction. The diagnosis of bipolar depression can be delayed by 8 to 10 years. The reason for this delay is mainly the fact that both manic and hypomanic episodes appear lately in the course of the disorder. It is therefore necessary to diagnose this clinical entity as early as possible versus monopolar depression in order to treat it more effectively. This differential diagnosis is based on certain clinical features of bipolar depression, which are often difficult to be distinguished from those of monopolar depression and therefore it is necessary to know specific criteria that differentiate them to some extent qualitatively and / or quantitatively. Such characteristics are daily mood swings, multiple physical complaints, psychomotor retardation, psychotic elements (delusions and perceptual disorders mood congruent or noncongruent), the disturbance of certain bodily functions, including circadian rhythms, sexual desire, appetite, and disorders of sleep architecture. The treatment of bipolar depression is based on the options known from monopolar depression (such as the use of antidepressants, antipsychotics, and certain antiepileptic agents) and their combinations, while in recent years it has been enriched with new pharmaceutical agents and non-pharmacological approaches. New glutaminergic regulators dominate the new pharmacological agents' research, and among them the antidepressant effect of ketamine and esketamine at sub-anesthetic doses is being extensively investigated during recent years. Non-pharmacological approaches include methods such as electroconvulsive therapy, repetitive transcranial magnetic stimulation (rTMS), sleep deprivation, and phototherapy.

Impairments in Peripheral Blood T Effector and T Regulatory Lymphocytes in Bipolar Disorder Are Associated with Staging of Illness and Anti-cytomegalovirus IgG Levels.

There is now evidence that, based on cytokine profiles, bipolar disorder (BD) is accompanied by simultaneous activation of the immune-inflammatory response system (IRS) and the compensatory immune-regulatory system (CIRS), and that both components may be associated with the staging of illness. Nevertheless, no BD studies have evaluated the IRS/CIRS ratio using CD (cluster of differentiation) molecules expressed by peripheral blood activated T effector (Teff) and T regulatory (Treg) subpopulations. This study examined Teff/Treg subsets both before and after ex vivo anti-CD3/CD28 stimulation using flow cytometric immunophenotyping in 25 symptomatic remitted BD patients and 21 healthy controls and assessed human cytomegalovirus (HCMV)-specific IgG antibodies. BD is associated with a significantly lowered frequency of unstimulated CD3 + CD8 + CD71+ and CD4 + CD25 + FOXP3 and increased CD4 + CD25 + FOXP3 + CD152+ frequencies and with lowered stimulated frequencies of CD3 + CD8 + CD71+, CD4 + CD25 + FOXP3 + CD152+, and CD4 + CD25 + FOXP3 + GARP cells and, consequently, by an increased stimulated Teff/Treg ratio. Moreover, the number of manic, but not hypomanic or depressive episodes, is significantly and negatively associated with the stimulated proportions of CD3 + CD4 + CD154+, and CD69+ and CD71+ expression on CD4+ and CD8+ cells, while duration of illness (≥ 10 years) is accompanied by a depleted frequency of stimulated CD152+ Treg, and CD154+ and CD71+ CD4+ T cells. BD and anti-human cytomegalovirus (HCMV) IgG levels significantly interact to decrease the expression of CD4 + CD25 + FOXP+GARP T phenotypes. In conclusion, in BD patients, immune injuries, staging, and HCMV seropositivity interact and cause CIRS dysfunctions and exaggerated IRS responses, which play a key role in parainflammation and neuroaffective toxicity. HCMV seropositivity contributes to an immune-risk phenotype in BD.

Antidepressant light therapy for bipolar patients: A meta-analyses.

BACKGROUNDS: Bipolar depression is still a very difficult to treat condition with low success rates of antidepressant drugs, high rates of morbidity and suicide risk and antidepressant-emergent mania risk. Despite a growing body of evidence has been generated over the last decade about Light Therapy (LT) as an effective treatment for depression the management of it continues to be a point of debate for Bipolar Disorder especially when considering non-seasonal pattern. METHODS: We systematically screened current literature using the PubMed electronic platform. We considered "mood disorder", "depression" and "light therapy" as keywords for the search. RESULTS: We retrieved 1907 papers. After the screening, we selected 11 papers to be included in the analysis, treating 195 patients affected by bipolar depression. 5 studies were RCT studies. The overall analysis, including non-RCTs, showed a positive effect of the treatment in all the included studies (ESs: -1.46, 95% CI:-1.677 to -1.242; p<0.001). A significant effect of LT compared to placebo was found also in RCTs (ESs: -0.501, 95% CI: - 0.777 to -0.225; p<0.001). LIMITATIONS: A high heterogeneity between the studies was found when including non-RCTs and the number of RCTs was small CONCLUSION: We confirmed the -efficacy of LT as antidepressant non-pharmacological therapy also in bipolar depression.

On maternal Post-Partum/Natal depression. A global underrecognized problem and the need for better Treatment strategies.

BACKGROUND: Maternal Postpartum (PPD) or Postnatal Depression (PND) is believed to be the commonest medical complication postpartum. Evidence suggests a significantly higher prevalence of the disease compared to the often reported 10-15%. METHOD: Studies were identified by accessing several databases including PubMed/Medline, PubMed Central, EBSCO, and PsycINFO. RESULTS: Vitamin D (VD) deficiency, hormonal levels alteration (estrogen, progesterone, testosterone, oxytocin, and prolactin), thyroid dysfunction, and increased oxidative stress, play a critical role in PPD etiopathogenesis and pathophysiology. CONCLUSIONS: Treatment strategies should include an integrated approach of antidepressants and psychotherapy, melatonin, diet, sleep improvement, exercise, VD and antioxidants supplementation, and economic and social support.

Salience-thalamic circuit uncouples in major depressive disorder, but not in bipolar depression.

BACKGROUND: Bipolar depression (BDD) and major depressive disorder (MDD) are two diseases both characterized by depressed mood and diminished interest or pleasure. Recent neuroimaging studies have implicated the thalamo-cortical circuit in mood disorders, and the present study aimed to map thalamo-cortical connectivity to explore the dissociable and common abnormalities between bipolar and major depression in this circuit. METHOD: Applying resting-state functional magnetic resonance imaging (fMRI), we mapped the thalamo-cortical circuit using a fine-grained thalamic atlas with 8 sub-regions bilaterally in 38 BDD patients, 42 MDD patients and 39 healthy controls (HCs). Correlation analysis was then performed between thalamo-cortical connectivity and clinical variables. RESULT: The findings showed that both patient groups exhibited prefronto-thalamo-cerebellar and sensorimotor-thalamic hypoconnectivity, while the abnormalities in MDD were more extensive. Particularly, MDD group showed decreased thalamic connectivity with the salience network including the insula, anterior cingulate cortex (ACC), and striatum. No correlations were found between the abnormal thalamo-cortical connectivity and clinical symptoms in either patient group. LIMITATION: Most patients in our study were taking drugs at the time of scanning, which may confound our findings. CONCLUSION: Our finding suggest that the thalamo-cortical hypofunction is a common neuro-substrate for BDD and MDD. Specifically, the hypoconnectivity between the thalamus and salience network including the insula, ACC and striatum may be a distinguished biomarker for MDD, which may help to differentiate these two emotional disorders.

Effectiveness of Sleep Deprivation in Treating Acute Bipolar Depression as Augmentation Strategy: A Systematic Review and Meta-Analysis.

BACKGROUND: Bipolar disorder is a disabling disease characterized by the recurrence of mood episodes. Successful strategies for the acute treatment of bipolar depression are still a matter of controversy. Total sleep deprivation (TSD) has shown acute antidepressant effect; however, the prompt relapse of depressive symptoms after sleep recovery has been reported. Taking this into consideration, we aimed to address a twofold research question: what are the acute effects of adding TSD to pharmacological treatment and what are the acute and chronic effects of adding medications to TSD. METHODS: MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov databases were searched for clinical trials assessing bipolar depression and TSD. Two independent reviewers selected and classified 90 abstracts. The outcomes we assessed were change in Hamilton Depression Rating Scale (HDRS) or Montgomery-Asberg Depression Rating Scale (MADRS), sustained long-term response rate, treatment-emergent mania or hypomania, and tolerability (using dropout rates as a proxy). The compared groups were: TSD alone versus TSD plus medications and medications alone versus medications plus TSD. Data was analyzed using Stata 16.0. RESULTS: Patients treated with TSD plus medications compared with medications alone showed a significant decrease in depressive symptomatology after one week (SMD -0.584 [95% CI -1.126 to -0.042], p = 0.03. Also, a significant decrease in depressive symptomatology (SMD -0.894 [95% CI -1.388 to -0.399], p < 0.001) was found in the group with TSD plus medications compared with TSD alone, at the 10th day of treatment. We meta-analyzed the long-term effect of the TSD. It showed a sustained antidepressant effect (log OR = 2.365 (95% CI 0.95 to 3.779, p < 0.001) in the group where TSD was combined with medication when compared with patients treated only with TSD. Finally, no differences in tolerability (log OR = 0.234 (95% CI -1.164 to 1.632, p = 0.74) or affective switch were found. CONCLUSION: Adding TSD to medications to bipolar depression treatment resulted in an augmentation in acute response. We also found that medications have a positive impact in acute response when added to TSD. Furthermore, this higher response rate was maintained after 3 months while keeping Lithium therapy.

Physical Activity as a Predictor of Clinical Trial Outcomes in Bipolar Depression: A Subanalysis of a Mitochondrial-Enhancing Nutraceutical Randomized Controlled Trial.

OBJECTIVES: Individuals with bipolar disorder (BD) generally engage in low levels of physical activity (PA), and yet few studies have investigated the relationship between PA and change in BD symptom severity. The aim of this subanalysis of an adjunctive nutraceutical randomized controlled trial for the treatment of bipolar depression was to explore the relationship between PA, the active adjunctive treatments (a nutraceutical "mitochondrial cocktail"), and clinical outcomes. METHODS: Participants with bipolar depression were randomized to receive N-acetylcysteine alone, N-acetylcysteine with a combination of nutraceuticals (chosen for the potential to increase mitochondrial activity), or placebo for 16 weeks. Participants (n = 145) who completed the International Physical Activity Questionnaire-Short Form (IPAQ-SF; measured at Week 4) were included in this exploratory subanalysis. Assessments of BD symptoms, functioning, and quality of life were completed at monthly visits up until Week 20. Generalised Estimating Equations were used to explore whether IPAQ-SF scores were a moderator of treatment received on outcomes of the study. RESULTS: Week-4 PA was not related to changes in Montgomery Åsberg Depression Rating Scale scores across the study until Week 20. However, participants who engaged in more PA and who received the combination treatment were more likely to have a reduction in scores on the Bipolar Depression Rating Scale (P = 0.03). However, this was not consistent in all domains explored using the IPAQ-SF. Participants who engaged in higher levels of PA also experienced greater improvement in social and occupational functioning and less impairment in functioning due to their psychopathology and improvement in quality of life at Week 20, irrespective of treatment. CONCLUSIONS: This study provides novel evidence of the association between PA and reduction in BD symptoms in a nutraceutical clinical trial. However, further research assessing the potential synergistic effects of PA in BD is required.

Lamotrigine as a mood stabilizer: insights from the pre-clinical evidence.

INTRODUCTION: Lamotrigine (LTG) is a well-established anticonvulsant that is also approved for the prevention of mood relapses in bipolar disorder. However, the mechanisms underlying LTG mood stabilizing effects remain unclear. Areas covered: Herein, the pre-clinical evidence concerning LTG's' mode of action in depression and mania is reviewed. Bottlenecks and future perspectives for this expanding and promising field are also discussed. Pre-clinical studies have indicated that neurotransmitter systems, especially serotoninergic, noradrenergic and glutamatergic, as well as non-neurotransmitter pathways such as inflammation and oxidative processes might play a role in LTG's antidepressant effects. The mechanisms underlying LTG's anti-manic properties remain to be fully explored, but the available pre-clinical evidence points out to the role of glutamatergic neurotransmission, possibly through AMPA-receptors. Expert opinion: A major limitation of current pre-clinical investigations is that there are no experimental models that recapitulate the complexity of bipolar disorder. Significant methodological differences concerning time and dose of LTG treatment, administration route, animal strains, and behavioral paradigms also hamper the reproducibility of the findings, leading to contradictory conclusions. Moreover, the role of other mechanisms (e.g. inositol phosphate and GSK3ß pathways) implicated in the mode of action of different mood-stabilizers must also be consolidated with LTG.

Bright Light Therapy in the Morning or at Mid-Day in the Treatment of Non-Seasonal Bipolar Depressive Episodes (LuBi): Study Protocol for a Dose Research Phase I / II Trial.

Objective This study protocol aims to determine, using a rigorous approach in patients with bipolar disorder (BD) and non-seasonal major depressive episode (MDE), the characteristics of bright light therapy (BLT) administration (duration, escalation, morning and mid-day exposures) depending on the tolerance (hypomanic symptoms). Methods Patients with BD I or II and treated by a mood stabilizer are eligible. After 1 week of placebo, patients are randomized between either morning or mid-day exposure for 10 weeks of active BLT with glasses using a dose escalation at 7.5, 10, 15, 30 and 45 minutes/day. A further follow-up visit is planned 6 months after inclusion. Patients will be included by cohorts of 3, with at least 3 days of delay between them, and 1 week between cohorts. If none meet a dose limiting toxicity (DLT; i.e hypomanic symptoms), the initiation dose of the next cohort will be increased. If one patient meet a DLT, an additionnal cohort will start at the same dose. If 2 or 3 patients meet a DLT, from the same cohort or from two cohorts at the same dose initiation, the maximum tolerated dose is defined. This dose escalation will also take into account DLTs observed during the intra-subject escalation on previous cohorts, with a "Target Ceiling Dose" defined if 2 DLTs occured at a dose. Discussion Using an innovative and more ergonomic device in the form of glasses, this study aims to better codify the use of BLT in BD to ensure a good initiation and tolerance. Trial registrationaaClinicalTrials.gov Identifier: NCT03396744.

Clinical efficacy, onset time and safety of bright light therapy in acute bipolar depression as an adjunctive therapy: A randomized controlled trial.

BACKGROUND: Bright light therapy (BLT) is an effective treatment for seasonal affective disorder and non- seasonal depression. The efficacy of BLT in treating patients with bipolar disorder is still unknown. AIMS: The aim of this study is to examine the efficacy, onset time and clinical safety of BLT in treating patients with acute bipolar depression as an adjunctive therapy (trial registration at ClinicalTrials.gov: NCT02009371). METHODS: This was a multi-center, single blind, randomized clinical trial. Seventy-four participants were randomized in one of two treatment conditions: BLT and control (dim red light therapy, dRLT). Sixty-three participants completed the study (33 BLT, 30 dRLT). Light therapy lasted for two weeks, one hour every morning. All participants were required to complete several scales assessments at baseline, and at the end of weeks 1 and 2. The primary outcome measures were the clinical efficacy of BLT which was assessed by the reduction rate of HAMD-17 scores, and the onset time of BLT which was assessed by the reduction rate of QIDS-SR16 scores. The secondary outcome measures were rates of switch into hypomania or mania and adverse events. RESULTS: 1) Clinical efficacy: BLT showed a greater ameliorative effect on bipolar depression than the control, with response rates of 78.19% vs. 43.33% respectively (p < 0.01). 2) Onset day: Median onset day was 4.33 days in BLT group. 3) BLT-emergent hypomania: No participants experienced symptoms of hypomania. 4) Side effects: No serious adverse events were reported. CONCLUSION: BLT can be considered as an effective and safe adjunctive treatment for patients with acute bipolar depression.

Bright Light Therapy in the Morning or at Mid-Day in the Treatment of Non-Seasonal Bipolar Depressive Episodes (LuBi): Study Protocol for a Dose Research Phase I / II Trial

OBJECTIVE: This study protocol aims to determine, using a rigorous approach in patients with bipolar disorder (BD) and non-seasonal major depressive episode (MDE), the characteristics of bright light therapy (BLT) administration (duration, escalation, morning and mid-day exposures) depending on the tolerance (hypomanic symptoms). METHODS: Patients with BD I or II and treated by a mood stabilizer are eligible. After 1 week of placebo, patients are randomized between either morning or mid-day exposure for 10 weeks of active BLT with glasses using a dose escalation at 7.5, 10, 15, 30 and 45 minutes/day. A further follow-up visit is planned 6 months after inclusion. Patients will be included by cohorts of 3, with at least 3 days of delay between them, and 1 week between cohorts. If none meet a dose limiting toxicity (DLT; i.e hypomanic symptoms), the initiation dose of the next cohort will be increased. If one patient meet a DLT, an additionnal cohort will start at the same dose. If 2 or 3 patients meet a DLT, from the same cohort or from two cohorts at the same dose initiation, the maximum tolerated dose is defined. This dose escalation will also take into account DLTs observed during the intra-subject escalation on previous cohorts, with a “Target Ceiling Dose” defined if 2 DLTs occured at a dose. DISCUSSION: Using an innovative and more ergonomic device in the form of glasses, this study aims to better codify the use of BLT in BD to ensure a good initiation and tolerance. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03396744.

The preclinical discovery and development of quetiapine for the treatment of mania and depression.

INTRODUCTION: Bipolar disorder is a chronic disabling condition characterized by alternating manic and depressive episodes. Bipolar disorder has been associated with functional impairment, poor quality of life, morbidity and mortality. Despite its significant clinical, social and economic burden, treatment options for bipolar disorder are still limited. Several clinical trials have shown efficacy of the atypical antipsychotic quetiapine (QTP) in the treatment of this condition. However, the mechanisms underlying the antidepressant and anti-manic effects of QTP remain poorly understood. Areas covered: The article provides the emerging evidence from pre-clinical studies regarding the antidepressant and anti-manic mechanisms of action of QTP. In combination with its primary active metabolite norquetiapine, QTP modulates several neurotransmitter systems, including serotonin, dopamine, noradrenaline and histamine. QTP also seems to influence mediators of the immune system. Expert opinion: Pre-clinical studies have provided valuable information on the potential antidepressant mechanisms of action of QTP, but pre-clinical studies on QTP's anti-manic effects are still scarce. A major problem refers to the lack of valid experimental models for bipolar disorder. Additionally, immune and genetic based studies are largely descriptive. The role of the QTP metabolite norquetiapine in modulating non-neurotransmitter systems also needs to be further addressed.

Psychotherapeutic Treatment of Bipolar Depression.

The gold standard for treating bipolar depression is based on the combination of mood stabilizers and psychotherapy. Therefore, the authors present evidence-based models and promising approaches for psychotherapy for bipolar depression. Cognitive-behavioral therapy, family focused therapy, interpersonal and social rhythm therapy, mindfulness-based cognitive therapy, and dialectical behavior therapy are discussed. Behavioral activation, the cognitive behavioral analysis system of psychotherapy, and the unified protocol as promising future directions are presented. This review informs medical providers of the most appropriate referral guidelines for psychotherapy for bipolar depression. The authors conclude with a decision tree delineating optimal referrals to each psychotherapy approach.

Sleep homeostatic pressure and PER3 VNTR gene polymorphism influence antidepressant response to sleep deprivation in bipolar depression.

BACKGROUND: Combined Total sleep deprivation (TSD) and light therapy (LT) cause a rapid improvement in bipolar depression which has been hypothesized to be paralleled by changes in sleep homeostasis. Recent studies showed that bipolar patients had lower changes of EEG theta power after sleep and responders to antidepressant TSD+LT slept less and showed a lower increase of EEG theta power then non-responders. A polymorphism in PER3 gene has been associated with diurnal preference, sleep structure and homeostatic response to sleep deprivation in healthy subjects. We hypothesized that the individual variability in the homeostatic response to TSD could be a correlate of antidepressant response and be influenced by genetic factors. METHODS: We administered three TSD+LT cycles to bipolar depressed patients. Severity of depression was rated on Hamilton Depression Rating Scale. Actigraphic recordings were performed in a group of patients. RESULTS: PER3 polymorphism influenced changes in total sleep time (F=2.24; p=0.024): while PER3(4/4) and PER3(4/5) patients showed a reduction in it after treatment, PER3(5/5) subjects showed an increase of about 40min, suggesting a higher homeostatic pressure. The same polymorphism influenced the change of depressive symptomatology during treatment (F=3.72; p=0.028). LIMITATIONS: Sleep information was recorded till the day after the end of treatment: a longer period of observation could give more information about the possible maintenance of allostatic adaptation. CONCLUSIONS: A higher sleep homeostatic pressure reduced the antidepressant response to TSD+LT, while an allostatic adaptation to sleep loss was associated with better response. This process seems to be under genetic control.