Molecular mechanisms of quetiapine bidirectional regulation of bipolar depression and mania based on network pharmacology and molecular docking: Evidence from computational biology.

BACKGROUND: Quetiapine monotherapy is recommended as the first-line option for acute mania and acute bipolar depression. However, the mechanism of action of quetiapine is unclear. Network pharmacology and molecular docking were employed to determine the molecular mechanisms of quetiapine bidirectional regulation of bipolar depression and mania. METHODS: Putative target genes for quetiapine were collected from the GeneCard, SwissTargetPrediction, and DrugBank databases. Targets for bipolar depression and bipolar mania were identified from the DisGeNET and GeneCards databases. A protein-protein interaction (PPI) network was generated using the String database and imported into Cytoscape. DAVID and the Bioinformatics platform were employed to perform the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses of the top 15 core targets. The drug-pathway-target-disease network was constructed using Cytoscape. Finally, molecular docking was performed to evaluate the interactions between quetiapine and potential targets. RESULTS: Targets for quetiapine actions against bipolar depression (126 targets) and bipolar mania (81 targets) were identified. Based on PPI and KEGG pathway analyses, quetiapine may affect bipolar depression by targeting the MAPK and PI3K/AKT insulin signaling pathways via BDNF, INS, EGFR, IGF1, and NGF, and it may affect bipolar mania by targeting the neuroactive ligand-receptor interaction signaling pathway via HTR1A, HTR1B, HTR2A, DRD2, and GRIN2B. Molecular docking revealed good binding affinity between quetiapine and potential targets. LIMITATIONS: Pharmacological experiments should be conducted to verify and further explore these results. CONCLUSIONS: Our findings suggest that quetiapine affects bipolar depression and bipolar mania through distinct biological core targets, and thus through different mechanisms. Furthermore, our results provide a theoretical basis for the clinical use of quetiapine and possible directions for new drug development.

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.

The use of sertraline to treat an adolescent of dystonia comorbid with major depressive disorder with psychotic features.

Dystonia is characterized by sustained or intermittent involuntary muscle contractions. Psychiatric symptoms are essential non-motor features of dystonia, and higher risks of depressive and anxiety disorders have been reported. The precedence of psychiatric to motor symptoms in some patients and the dopaminergic and serotonergic system involvement in both the motor and psychiatric aspects suggest these psychiatric disorders may be intrinsic to the neurobiology of dystonia. Nevertheless, psychiatric comorbidities are often construed as secondary reactions to motor disabilities and the negative bio-psycho-social impacts of dystonia, leading to underdiagnosis and undertreatment. Research on antidepressant use in dystonia is scarce, especially in children and adolescents. This report presents a 17-year-old female with dystonia comorbid with depression with psychotic features, whose motor symptoms improved but psychiatric symptoms persisted with dopaminergic pharmacotherapy. Sertraline was finally added 5 years after the onset and successfully managed her psychotic depression without worsening motor symptoms. Early detection, prompt diagnosis, and timely holistic treatment with dopaminergic agents, antidepressants, and psychosocial interventions are critical for the mental health of dystonia patients.

[Nimodipine in treatment of bipolar disorder]. / Primenenie nimodipina v terapii bipolyarnogo affektivnogo rasstroistva.

The purpose of this review is to correlate current data on the molecular mechanisms of action of the drug Nimodipine with its clinical effects and applicability in mental disorders belonging to the spectrum of affective pathology. The article discusses the prospects for using the calcium channel blocker nimodipine as a method of both mono and combination therapy for bipolar disorders with various types of course. Nimodipine is a selective blocker of voltage-dependent calcium channels, a dihydropyridine derivative. By blocking L type calcium channels, it prevents the entry of calcium ions into the cell. Due to its pronounced ability to penetrate the blood-brain barrier, it has a selective effect on brain neurons and has a vasodilating, antihypertensive and normotimic effect. Nimodipine blocks LTCC channels in brain neurons, thereby influencing synaptic plasticity, transmitter release and excitation-transcription coupling, which makes it possible to influence various clinical conditions with pathology in the area of affect, including bipolar disorders with ultra-rapid cycling, and also, in cases with high resistance and intolerance to other mood stabilizers.

Preliminary results from the Australian Genetics of Bipolar Disorder Study: A nation-wide cohort.

OBJECTIVE: The Australian Genetics of Bipolar Disorder Study is a nation-wide cohort of adults living with bipolar disorder. The study aims to detect the relationships between genetic risk, symptom severity, and the lifetime prevalence of bipolar disorder, treatment response and medication side effects, and patterns and costs of health care usage. METHODS: A total of 6682 participants (68.3% female; aged 44.8 ± 13.6 years [range = 18-90]) were recruited in three waves: a nation-wide media campaign, a mail-out based on prescriptions for lithium carbonate and through the Australian Genetics of Depression Study. Participants completed a self-report questionnaire. A total of 4706 (70%) participants provided a saliva sample and were genotyped and 5506 (82%) consented to record linkage of their Pharmaceutical and Medicare Benefits Schedule data. RESULTS: Most participants were living with bipolar I disorder (n = 4068) while 1622 participants were living with bipolar II disorder and 992 with sub-threshold bipolar disorder. The mean age of bipolar disorder diagnosis was 32.7 ± 11.6 years but was younger in bipolar I (p = 2.0E-26) and females (p = 5.7E-23). Excluding depression with onset prior to bipolar disorder diagnosis, 64.5% of participants reported one or more co-occurring psychiatric disorders: most commonly generalised anxiety disorder (43.5%) and posttraumatic stress disorder (20.7%). Adverse drug reactions were common and resulted in discontinuation rates ranging from 33.4% for lithium to 63.0% for carbamazepine. CONCLUSION: Our findings highlight the high rate of comorbidities and adverse drug reactions among adults living with bipolar disorder in the general Australian population. Future genomic analyses focus on identifying genetic variants influencing pharmacotherapy treatment response and side effects.

Older age bipolar disorder.

PURPOSE OF REVIEW: Older age bipolar disorder (OABD) refers to patients with bipolar disorder aged 50 years and over. There is a paucity of evidence-based guidelines specific to OABD, but in recent years, several studies have been published on OABD. The current review synthesizes previous literature (up to January 1, 2021) as well as most recent literature on OABD (since January 1, 2021). RECENT FINDINGS: This review covers the following themes: diagnosis and specifiers, clinical course, psychosocial functioning, cognition, physical comorbidities, and pharmacotherapy. On the basis of the latest data, specific clinical recommendations are proposed for each theme. SUMMARY: OABD forms a more complex subgroup of bipolar disorder, with an increased risk of cognitive deficits, physical comorbidities, impaired psychosocial functioning, and premature death. The distinctions between BD-I and BD-II and between EOBD and LOBD do not clinically represent relevant subtypes for OABD patients. Mental healthcare professionals should treat all OABD patients with an integrative care model that takes into account cognitive and physical comorbidities and that contains elements aimed at improvement of psychosocial functioning and quality of life. Older age itself should not be a reason to withhold lithium treatment. Future research should collect data on essential data domains using validated measurement scales.

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.

Does celecoxib with sodium valproate have an augmentation effect on acute mania in bipolar disorder? A double-blind controlled clinical trial in Iran.

Inflammatory processes in the brain play a role in acute mania etiopathogenesis. There is little evidence indicating the efficacy of celecoxib adjuvant therapy in treatmenting of manic episodes of bipolar disorder. Therefore, this clinical trial aimed to assess the celecoxib effect on treating acute mania. In a double-blind, placebo-controlled trial, 58 patients meeting the criteria for acute mania were enrolled. After considering eligibility, 45 patients were included in the study and randomly divided into two groups. The first group (23 patients) received sodium valproate 400 mg/day along with celecoxib 400 mg/day, and the second group (22 patients) received sodium valproate 400 mg/day and a placebo. The subjects were evaluated by the Young Mania Rating Scale (YMRS) at the beginning of the study and 9, 18, and 28 days following the initiation of the medication. Evaluation of baseline factors indicated a significant difference in age ( P = 0.01) and psychiatric history ( P = 0.02) between the two groups. However, other factors were similar between groups ( P ≥ 0.05). Comparing the YMRS score between celecoxib and placebo groups revealed no significant difference on days 0, 9, 18, and 28. However, the YMRS score at the end of the study decreased by 16.05 ± 7.65 in the intervention group ( P < 0.001) and 12.50 ± 5.98 in controls ( P < 0.001) compared to the baseline, the trend of change was not significant between the two groups during the time of the study ( F = 0.38; P = 0.84). Although celecoxib adjuvant therapy indicated no considerable side effects, a longer treatment duration may be needed to detect its beneficial effects for treating acute mania in bipolar patients. Trial registration: Iran clinical trial register: IRCT20200306046708N1.

Therapy of replenishing and regulating for manic episode in bipolar disorder: study protocol for a prospective, double-blind, randomized controlled trial.

Bipolar disorder (BD) is a chronic and recurrent disorder characterized by biphasic mood episodes of mania or hypomania and depression. It affects more than 1% of the global population and is a leading cause of disability in young people. Currently available treatments for BD are still fairly limited in terms of efficacy, with high rates of non-adherence, non-response, and undesirable side effects. Traditional Chinese medicine (TCM) has a long history and rich experience in stabilizing mania and improving quality of life. Aiming at rebalancing and in BD, therapy of replenishing and regulating (RYRY therapy) has been in clinical use for years in China. The present prospective, double-blind, randomized controlled trial is designed to investigate the efficacy and safety of RYRY therapy for bipolar mania and its possible mechanism from the point of regulating gut microbiota and anti-inflammation. A total of 60 eligible participants will be recruited from Beijing Anding Hospital. They will be randomized to either the study group or the control group in a ratio of 1∶1. Participants allocated to the study group will receive RYRY granule, while placebo granule will be applied in the control group. Participants in both groups will be prescribed conventional therapy for manic episode in BD. Four scheduled visits will be conducted over 4 weeks. Outcome measurements include Young Mania Rating Scale, TCM Symptom Pattern Rating Scale, Treatment Emergent Symptom Scale, levels of C-reactive protein, interleukin-6 and tumor necrosis factor-α and the gut microbial community profile of stool samples. Safety outcomes and adverse events will also be recorded. In this study, we set a number of scientific and objective assessments to evaluate the efficacy of RYRY therapy and study into its possible mechanism, hopefully offering clinicians an alternative approach to BD.

Valproate and lithium: Old drugs for new pharmacological approaches in brain tumors?

Beyond its use as an antiepileptic drug, over time valproate has been increasingly used for several other therapeutic applications. Among these, the antineoplastic effects of valproate have been assessed in several in vitro and in vivo preclinical studies, suggesting that this agent significantly inhibits cancer cell proliferation by modulating multiple signaling pathways. During the last years various clinical trials have tried to find out if valproate co-administration could enhance the antineoplastic activity of chemotherapy in glioblastoma patients and in patients suffering from brain metastases, demonstrating that the inclusion of valproate in the therapeutic schedule causes an improved median overall survival in some studies, but not in others. Thus, the effects of the use of concomitant valproate in brain cancer patients are still controversial. Similarly, lithium has been tested as an anticancer drug in several preclinical studies mainly using the unregistered formulation of lithium chloride salts. Although, there are no data showing that the anticancer effects of lithium chloride are superimposable to the registered lithium carbonate, this formulation has shown preclinical activity in glioblastoma and hepatocellular cancers. However, few but interesting clinical trials have been performed with lithium carbonate on a very small number of cancer patients. Based on published data, valproate could represent a potential complementary therapeutic approach to enhance the anticancer activity of brain cancer standard chemotherapy. Same advantageous characteristics are less convincing for lithium carbonate. Therefore, the planning of specific phase III studies is necessary to validate the repositioning of these drugs in present and future oncological research.

An update on potential pharmacotherapies for cognitive impairment in bipolar disorder.

INTRODUCTION: Cognitive impairment is a core feature of bipolar disorder (BD) that impedes recovery by preventing the return to optimal socio-occupational functioning and reducing quality of life. Presently, there are no efficacious treatments for cognitive impairment in BD, but many pharmacological interventions are being considered as they have the potential to target the underlying pathophysiology of the disorder. AREAS COVERED: This review summarizes the available evidence for pharmacological interventions for cognitive impairment in bipolar disorder. We searched PubMed, MedLine, and PsycInfo from inception to December 1st, 2022. Traditional treatments, such as lithium, anticonvulsants (lamotrigine), antipsychotics (aripiprazole, asenapine, cariprazine, lurasidone, and olanzapine), antidepressants (vortioxetine, fluoxetine, and tianeptine) and psychostimulants (modafinil), and emerging interventions, such as acetylcholinesterase inhibitors (galantamine and donepezil), dopamine agonists (pramipexole), erythropoietin, glucocorticoid receptor antagonists (mifepristone), immune modulators (infliximab, minocycline and doxycycline), ketamine, metabolic agents (insulin, metformin, and liraglutide), probiotic supplements, and Withania somnifera are discussed. EXPERT OPINION: The investigation of interventions for cognitive impairment in BD is a relatively under-researched area. In the past, methodological pitfalls in BD cognition trials have also been a critical limiting factor. Expanding on the existing literature and identifying novel pharmacological and non-pharmacological treatments for cognitive impairment in BD should be a priority.

Does circadian dysrhythmia drive the switch into high- or low-activation states in bipolar I disorder?

OBJECTIVES: Emerging evidence suggests a role of circadian dysrhythmia in the switch between "activation" states (i.e., objective motor activity and subjective energy) in bipolar I disorder. METHODS: We examined the evidence with respect to four relevant questions: (1) Are natural or environmental exposures that can disrupt circadian rhythms also related to the switch into high-/low-activation states? (2) Are circadian dysrhythmias (e.g., altered rest/activity rhythms) associated with the switch into activation states in bipolar disorder? (3) Do interventions that affect the circadian system also affect activation states? (4) Are associations between circadian dysrhythmias and activation states influenced by other "third" factors? RESULTS: Factors that naturally or experimentally alter circadian rhythms (e.g., light exposure) have been shown to relate to activation states; however future studies need to measure circadian rhythms contemporaneously with these natural/experimental factors. Actigraphic measures of circadian dysrhythmias are associated prospectively with the switch into high- or low-activation states, and more studies are needed to establish the most relevant prognostic actigraphy metrics in bipolar disorder. Interventions that can affect the circadian system (e.g., light therapy, lithium) can also reduce the switch into high-/low-activation states. Whether circadian rhythms mediate these clinical effects is an unknown but valuable question. The influence of age, sex, and other confounders on these associations needs to be better characterised. CONCLUSION: Based on the reviewed evidence, our view is that circadian dysrhythmia is a plausible driver of transitions into high- and low-activation states and deserves prioritisation in research in bipolar disorders.

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.

Nutraceuticals in mood disorders: current knowledge and future directions.

PURPOSE OF REVIEW: There is a large evidence base of clinical trials that have investigated the efficacy of a range of nutraceuticals on mood disorders. The aim of the current review is to provide an update regarding the efficacy and safety of nutraceutical agents in mood disorders and to highlight considerations for future research. RECENT FINDINGS: Nutraceuticals such as omega-3, probiotics, zinc, saffron and curcumin have been recommended as adjunctive interventions to standard treatments for people with depression, while St John's wort has been recommended as a monotherapy. In contrast, less research has been devoted to investigating the effect of nutraceuticals in bipolar disorder, with omega-3 being weakly recommended as an adjunctive to standard treatments. Although the safety profile of most nutraceuticals appears acceptable, more insight into the long-term effects within a range of cohorts is recommended. SUMMARY: There are a number of nutraceuticals that have clinical trial support for their use as either adjunctive interventions for depression; however, there is mostly limited support for their use in bipolar disorder. Further randomized controlled trials that take into consideration a number of emerging mechanisms, potential nutraceutical combinations and factors that may predict treatment response are required to inform clinical use.

Lurasidone use in Cannabis-Induced Psychosis: A Novel Therapeutic Strategy and Clinical Considerations in Four Cases Report.

BACKGROUND: Lurasidone is an atypical antipsychotic approved for the acute and maintenance treatment of schizophrenia. Recently, lurasidone was also extended FDA approval for adults with major depressive episodes associated with bipolar I disorder (bipolar depression), as either a monotherapy or as adjunctive therapy with lithium or valproate. The use of low doses of atypical antipsychotics is an essential component of early intervention in psychosis, but little has yet been studied on first episode cannabis-induced psychosis. For its particular performance and tolerability, lurasidone is becoming an important option for the treatment of first-episode psychosis in youth. Case presentation four patients experiencing first cannabis-induced psychotic episode were treated with lurasidone. In all patients, there was an improvement in the clinical picture of psychosis. The recovery was positive, not only with the remission of positive and negative symptoms, but also regarding disruptive behaviour, with the return of functioning. All the patients were treated with lurasidone, with a target dose of 74-128 mg/day. No significant side effects were reported. CONCLUSION: There are non-controlled studies for the use of lurasidone in first episode psychosis cannabis induced. These findings suggest that lurasidone is an atypical antipsychotic beneficial in this clinical picture. Treatment with medium-high doses of lurasidone could be effective and tolerable in this phase of the disorder. Randomized control trials with longer follow-up are recommended to confirm these positive results.

Vanadium in Bipolar Disorders-Reviving an Old Hypothesis.

Bipolar disorder (BD) is a severe and common chronic mental illness. The biological basis of the disease is poorly understood and its treatment is unsatisfactory. Our previous studies supported the notion that alterations in Na+, K+-ATPase activity were involved in the etiology of BD. As various chemical elements inhibit Na+, K+-ATPase, we determined the concentration of 26 elements in the serum of BD patients before and after treatment and in postmortem brain samples from BD patients, and compared them with matched controls. The only element that was reduced significantly in the serum following treatment was vanadium (V). Furthermore, the concentration of V was significantly lower in the pre-frontal cortex of BD patients compared with that of the controls. Intracerebroventricular administration of V in mice elicited anxiolytic and depressive activities, concomitantly inhibited brain Na+, K+-ATPase activity, and increased extracellular signal-regulated kinase phosphorylation. A hypothesis associating V with BD was set forth decades ago but eventually faded out. Our results are in accord with the hypothesis and advocate for a thorough examination of the possible involvement of chemical elements, V in particular, in BD.

A Randomized, Double-Blind, Controlled Clinical Trial of Omega-3 Fatty Acids and Inositol as Monotherapies and in Combination for the Treatment of Pediatric Bipolar Spectrum Disorder in Children Age 5-12.

Objectives: The aim of this study was to assess the efficacy and tolerability of omega-3 fatty acids (FAs) and inositol alone and in combination for the treatment of pediatric bipolar (BP) spectrum disorder in young children. Methods: Participants were male and female children ages 5-12 meeting DSM-IV diagnostic criteria for a BP spectrum disorder and displaying mixed, manic, or hypomanic symptoms without psychotic features at the time of evaluation. Results: Participants concomitantly taking psychotropic medication were excluded from efficacy analyses. There were significant reductions in YMRS and HDRS mean scores in the inositol and combination treatment groups (all p < 0.05) and in CDRS mean scores in the combination treatment group (p < 0.001), with the largest changes seen in the combination group. Those receiving the combination treatment had the highest rates of antimanic and antidepressant response. The odds ratios for the combination group compared to the omega-3 FAs and inositol groups were clinically meaningful (ORs ≥2) for 50% improvement on the YMRS, normalization of the YMRS (score <12) (vs. inositol group only), 50% improvement on the HDRS, 50% improvement on CDRS (vs. omega-3 FAs group only), and CGI-I Mania, CGI-I MDD, and CGI-I Anxiety scores <2. Conclusion: The antimanic and antidepressant effects of the combination treatment of omega-3 FAs and inositol were consistently superior to either treatment used alone. This combination may offer a safe and effective alternative or augmenting treatment for youth with BP spectrum disorder, but more work is needed to confirm the statistical significance of this finding.

Antidepressant chronotherapeutics normalizes prefrontal 1H-MRS glutamate in bipolar depression.

BACKGROUND: 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. METHODS: We studied single voxel 1H-MRS measures of DLPFC Glu and Glx levels of 48 healthy participants and 55 inpatients with a major depressive episode in course of Bipolar Disorder, a subset of which (N = 23) underwent three cycles of repeated TSD + LT and were evaluated before and after treatment. Treatment effects of mood and on Glu and Glx concentrations were analyzed in the context of the Generalized Linear Model (GLM), correcting for age, sex and ongoing lithium treatment. RESULTS: Higher 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 χ2 = 4.619, p = 0.0316) and in Glx levels (LR χ2 = 4.486, p = 0.0341). CONCLUSION: A 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.

Experimental data on lithium salts: From neuroprotection to multi-organ complications.

Lithium-salts stand on the first line of therapy for the management of specific psychiatric conditions, mainly bipolar mood disorder. It is also known to protect the brain against neurodegenerative processes such as Alzheimer's disease. Despite the mentioned merits, recent studies have revealed that high dose or prolonged lithium intake deteriorate the function of multiple key organs including heart, ovaries, thyroid gland and kidneys. Mechanistically, both positive and negative effects of lithium are mediated through methylation of ß-catenin nuclear-binding proteins which is potentiated by lithium-induced inhibition of GSK-3 or inositol monophosphatase. The current study briefly reviews the recent experimental data on lithium therapy considering both positive (i.e., neuroprotective) and negative aspects. In this regard, the question is that whether doses of lithium administered in experimental research are comparable with the therapeutic doses, as currently prescribed in clinical practice. It should be noted that the experimental data on animal studies, as widely reviewed here, could not be directly generalized to clinic. This is mainly because lithium doses applied in animal models are usually higher than therapeutic doses, however, there are evidence indicating that even animal to human translated doses of lithium, cause serious complications and this has been reported by meta-analyses on human studies. Therefore, we suggest the clinicians to use lithium-salts with precaution particularly in pregnancy and precisely adjust lithium concentration considering the patient's general health status to avoid lithium toxicity. Indeed, alternative approaches are recommended when the subject is pregnant, prolonged therapy is required or specific organ dysfunction is diagnosed.