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.

Lithium and Therapeutic Targeting of GSK-3.

Lithium salts have been in the therapeutic toolbox for better or worse since the 19th century, with purported benefit in gout, hangover, insomnia, and early suggestions that lithium improved psychiatric disorders. However, the remarkable effects of lithium reported by John Cade and subsequently by Mogens Schou revolutionized the treatment of bipolar disorder. The known molecular targets of lithium are surprisingly few and include the signaling kinase glycogen synthase kinase-3 (GSK-3), a group of structurally related phosphomonoesterases that includes inositol monophosphatases, and phosphoglucomutase. Here we present a brief history of the therapeutic uses of lithium and then focus on GSK-3 as a therapeutic target in diverse diseases, including bipolar disorder, cancer, and coronavirus infections.

Lithium treatment in the era of personalized medicine.

In 1949, an Australian psychiatrist, John Cade, reported on the antimanic efficacy of lithium carbonate, which is regarded as an introduction of lithium into contemporary psychiatry. Since the 1960s, lithium has been a precursor of mood stabilizers and has become first-choice drug for the prevention of affective episodes in mood disorders. For nearly four decades, lithium has also been used for the augmentation of antidepressant drugs in treatment-resistant depression. The knowledge of clinical and biological factors connected with the capability of long-term lithium treatment to prevent manic and depressive recurrences makes an important element of the personalized medicine of mood disorders. Excellent prophylactic lithium responders can be characterized by distinct mood episodes, with full remissions between them, the absence of other psychiatric morbidity, and the family history of bipolar illness. In recent years, many other clinical and biological factors connected with such a response have been identified, helping to select the best candidates for lithium prophylaxis. The antisuicidal effect of lithium during its long-term administration has been demonstrated and should also be taken into account as the element of personalized medicine for the pharmacological prophylaxis of patients with mood disorders. Several studies pertaining to personalized medicine were also dedicated to lithium treatment of acute mood episodes. Lithium still has a value in the treatment of mania and bipolar depression. However, it seems that the more important indication would be the augmentation of antidepressant drugs in treatment-resistant depression. The factors connected with the efficacy of lithium in these conditions are reviewed.

Lithium response in bipolar disorder correlates with improved cell viability of patient derived cell lines.

Lithium is an effective, well-established treatment for bipolar disorder (BD). However, the mechanisms of its action, and reasons for variations in clinical response, are unclear. We used neural precursor cells (NPCs) and lymphoblastoid cell lines (LCLs), from BD patients characterized for clinical response to lithium (using the "Alda scale" and "NIMH Retrospective Life chart method"), to interrogate cellular phenotypes related to both disease and clinical lithium response. NPCs from two biologically related BD patients who differed in their clinical response to lithium were compared with healthy controls. RNA-Seq and analysis, mitochondrial membrane potential (MMP), cell viability, and cell proliferation parameters were assessed, with and without in vitro lithium. These parameters were also examined in LCLs from 25 BD patients (16 lithium responders and 9 non-responders), and 12 controls. MMP was lower in both NPCs and LCLs from BD; but it was reversed with in vitro lithium only in LCLs, and this was unrelated to clinical lithium response. The higher cell proliferation observed in BD was unaffected by in vitro lithium. Cell death was greater in BD. However, LCLs from clinical lithium responders could be rescued by addition of in vitro lithium. In vitro lithium also enhanced BCL2 and GSK3B expression in these cells. Our findings indicate cellular phenotypes related to the disease (MMP, cell proliferation) in both NPCs and LCLs; and those related to clinical lithium response (cell viability, BCL2/GSK3B expression) in LCLs.

Cannabis use in early adulthood is prospectively associated with prescriptions of antipsychotics, mood stabilizers, and antidepressants.

OBJECTIVE: Cannabis is an acknowledged risk factor for some mental disorders, but for others the evidence is inconclusive. Prescribed medicinal drugs can be used as proxies for mental disorders. In this study, we investigate how use of cannabis is prospectively related to prescription of antipsychotics, mood stabilizers, antidepressants, and anxiolytics. METHODS: Data on cannabis exposure and relevant confounders were obtained from 2,602 individuals in the longitudinal Young in Norway Study, providing survey data from four data collection waves between 1992 and 2006. Data were coupled with information about prescriptions for psychotropic drugs from the Norwegian Prescription Database between 2007 and 2015. RESULTS: Past year cannabis use increased the risk of prescription of antipsychotics (OR = 5.56, 95 % CI 1.64 - 18.87), mood stabilizers (OR = 5.36, 95 % CI 1.99 - 14.44) and antidepressants (OR = 2.10, 95 % CI 1.36 - 3.25), after accounting for sociodemographic variables, conduct problems, additional drug use, mental distress, and prescriptions the year before cannabis use was measured. CONCLUSIONS: In this study of young adults from the general population, past year cannabis use was associated with later prescriptions of antipsychotics, mood stabilizers, and antidepressants.

The chronotherapeutic treatment of bipolar disorders: A systematic review and practice recommendations from the ISBD task force on chronotherapy and chronobiology.

AIMS: To systematically review the literature on the efficacy and tolerability of the major chronotherapeutic treatments of bipolar disorders (BD)-bright light therapy (LT), dark therapy (DT), treatments utilizing sleep deprivation (SD), melatonergic agonists (MA), interpersonal social rhythm therapy (IPSRT), and cognitive behavioral therapy adapted for BD (CBTI-BP)-and propose treatment recommendations based on a synthesis of the evidence. METHODS: PRISMA-based systematic review of the literature. RESULTS: The acute antidepressant (AD) efficacy of LT was supported by several open-label studies, three randomized controlled trials (RCTs), and one pseudorandomized controlled trial. SD showed rapid, acute AD response rates of 43.9%, 59.3%, and 59.4% in eight case series, 11 uncontrolled, studies, and one RCT, respectively. Adjunctive DT obtained significant, rapid anti-manic results in one RCT and one controlled study. The seven studies on MA yielded very limited data on acute antidepressant activity, conflicting evidence of both antimanic and maintenance efficacy, and support from two case series of improved sleep in both acute and euthymic states. IPSRT monotherapy for bipolar II depression had acute response rates of 41%, 67%, and 67.4% in two open studies and one RCT, respectively; as adjunctive therapy for bipolar depression in one RCT, and efficacy in reducing relapse in two RCTs. Among euthymic BD subjects with insomnia, a single RCT found CBTI-BP effective in delaying manic relapse and improving sleep. Chronotherapies were generally safe and well-tolerated. CONCLUSIONS: The outcome literature on the adjunctive use of chronotherapeutic treatments for BP is variable, with evidence bases that differ in size, study quality, level of evidence, and non-standardized treatment protocols. Evidence-informed practice recommendations are offered.

Use of "Lights" for Bipolar Depression.

PURPOSE: In this review, we will review the background and diagnosis of bipolar disorder (BD); describe the efficacy data and potential circadian and neural mechanisms underlying the effects of bright light for bipolar depression; and discuss the implementation of light therapy in clinical practice. RECENT FINDINGS: To date, morning bright light is the most widely tested form of light therapy for all mood disorders. Clinical trial reports suggest that midday or morning bright light treatment and novel chronotherapeutic interventions are effective for bipolar depression. Mechanisms of response may relate to effects on the circadian system and other changes in neural functioning. Using bright light to manage depressive symptoms in BD is reasonable but also requires concurrent antimanic treatment and careful clinical monitoring for response, safety, and mood polarity switch.

Pharmacotherapies for co-occurring substance use and bipolar disorders: A systematic review.

OBJECTIVES: Substance use disorders (SUDs), including those for alcohol, stimulants, tobacco, opioids and cannabis, in patients with bipolar disorder are a major clinical and public health problem, and are present in the majority of these patients. Nonetheless, the development of effective pharmacological treatments for co-occurring SUDs in bipolar illness have not been well-developed and may be an important practical reason for the reduced effectiveness of these medications in community practice. METHODS: We conducted a systematic review of the literature (PubMed, Medline, Google Scholar), and identified N = 29 clinical studies, which evaluated both mental health and SUD outcomes in patients with co-occurring bipolar disorders and SUDs. RESULTS: Our findings suggest the potential of valproate sodium and lamotrigine as preferred pharmacological agents for the treatment of co-occurring psychiatric and substance use outcomes in these patients. However, many of the reviewed studies are of open-label designs and of modest sample sizes. CONCLUSIONS: Thus, given the gaps in our knowledge, recommendations for treatment of this common and important co-morbidity are preliminary. Accordingly, the conduct of larger, randomized controlled trials for this co-morbidity is clearly needed.

Harmala Alkaloids Identify Ayahausca Intoxication in a Urine Drug Screen.

BACKGROUND: Ayahausca is an ethnobotanical drink of South America and the compound dimethyltryptamine (DMT) is primarily responsible for the hallucinogenic effects. DMT has a short half-life and its detection in urinary drug screens is challenging. We investigate a simple alternate approach to detect ayahuasca consumption by relying on other constituents of the drink, the ß-carboline harmala alkaloids. METHODS: Three commercially sourced harmala alkaloids were characterized and added to a non-targeted high-resolution mass spectrometry urine drug screening method. All analyses were performed on a Waters Xevo G2-XS LC-QTof, in positive electrospray ionization mode. The mass detector was operated in MSE mode and data processed with UNIFI™ software. A urine specimen from a patient suspected to have consumed ayahuasca was analyzed by a non-targeted drug screen. RESULTS: The harmala alkaloids: harmine, harmaline and tetrohydroharmaline (THH) were characterized and their detection data added to the toxicology screening library. Harmaline and THH were detected in the patient's urine specimen. CONCLUSION: The inclusion of the harmala alkaloids into the drug screen method library may enable the detection of ayahuasca use in patients that undergo non-targeted drug screen.

Missed opportunities in antenatal care for improving the health of pregnant women and newborns in Geita district, Northwest Tanzania.

BACKGROUND: Despite the significant benefits of early detection and management of pregnancy related complications during antenatal care (ANC) visits, not all pregnant women in Tanzania initiate ANC in a timely manner. The primary objectives of this research study in rural communities of Geita district, Northwest Tanzania were: 1) to conduct a population-based study that examined the utilization and availability of ANC services; and 2) to explore the challenges faced by women who visited ANC clinics and barriers to utilization of ANC among pregnant women. METHODS: A sequential explanatory mixed method design was utilized. Household surveys that examined antenatal service utilization and availability were conducted in 11 randomly selected wards in Geita district. One thousand, seven hundred and nineteen pregnant women in their 3rd trimester participated in household surveys. It was followed by focus group discussions with community health workers and pregnant women that examined challenges and barriers to ANC. RESULTS: Of the pregnant women who participated, 86.74% attended an ANC clinic at least once; 3.62% initiated ANC in the first trimester; 13.26% had not initiated ANC when they were interviewed in their 3rd trimester. Of the women who had attended ANC at least once, the majority (82.96%) had been checked for HIV status, less than a half (48.36%) were checked for hemoglobin level, and only a minority had been screened for syphilis (6.51%). Among women offered laboratory testing, the prevalence of HIV was 3.88%, syphilis, 18.57%, and anemia, 54.09%. In terms of other preventive measures, 91.01% received a tetanus toxoid vaccination, 76.32%, antimalarial drugs, 65.13%, antihelminthic drugs, and 76.12%, iron supplements at least once. Significant challenges identified by women who visited ANC clinics included lack of male partner involvement, informal regulations imposed by health care providers, perceived poor quality of care, and health care system related factors. Socio-cultural beliefs, fear of HIV testing, poverty and distance from health clinics were reported as barriers to early ANC utilization. CONCLUSION: Access to effective ANC remains a challenge among women in Geita district. Notably, most women initiated ANC late and early initiation did not guarantee care that could contribute to better pregnancy outcomes.

The Impact of Psychotropic Medications on Bone Health in Youth.

PURPOSE OF REVIEW: Psychotropics are prescribed to youth at rapidly growing rates and may negatively impact bone health. Little awareness exists of this association among prescribing providers. Childhood and adolescence are critical times for bone development. Understanding these effects and their management is important to informed psychotropic use. RECENT FINDINGS: Through a variety of mechanisms, antidepressants, benzodiazepines, mood stabilizers, neuroleptics, and stimulants may all negatively impact pediatric bone health. This confers added risk of osteoporosis in a population already at high risk for suboptimal bone health. Awareness of psychotropic-mediated effects on pediatric bone development is clinically relevant to the use and monitoring of these agents. Clinicians can manage these effects through informed consent, vitamin D supplementation, lifestyle modifications, and reducing polypharmacy. For mood stabilizers, vitamin D level monitoring and secondary prevention is indicated. Future longitudinal studies and development of monitoring guidelines regarding psychotropic impact on bone health are necessary.

Severe hair loss associated with psychotropic drugs in psychiatric inpatients-Data from an observational pharmacovigilance program in German-speaking countries.

BACKGROUND: The study aimed to investigate severe hair loss related to psychotropic drugs (PDs) by using data from the drug safety programme Arzneimittelsicherheit in der Psychiatrie (AMSP). METHODS: Data on PD utilization and reports of severe PD-related hair loss were collected in 83 psychiatric hospitals in Austria, Germany and Switzerland during the period 1993-2013. RESULTS: Out of 432,215 patients under surveillance, 404,009 patients were treated with PDs for the main indications of depression, schizophrenic disorder, neurosis, mania, and organic psychosis. Severe hair loss related to PD treatment was reported in 43 cases (0.01%). The rates of hair loss under antipsychotic drugs were slightly lower than the mean rates of all PDs and antidepressant drugs. Valproic acid was related to the highest risk. In 6 of the 43 cases, hair loss was imputed to multiple drugs, with 4 cases imputed to double drug combinations and 2 cases to triple combinations. Rates of severe hair loss under valproic acid (VPA) and lithium salts were distinctly lower as compared with the overall rates reported in literature. Severe hair loss under PD treatment was reported significantly more often in female patients than in male patients (p < 0.01). CONCLUSION: The rate of severe PD-related hair loss was very low in the present survey. The large number of patients included in this multicentre study allows for assessment and comparison of hair loss rates related to different PDs and groups of PDs and provides new and supplementary information on PD-related hair loss.

Factors affecting time to remission for inpatients with bipolar mania - A naturalistic Taiwanese study.

BACKGROUND: Bipolar disorder is a complicated and chronic mental disorder. This study investigated factors affecting time to remission for inpatients with bipolar mania after 4 weeks of acute treatment. METHODS: This naturalistic study recruited inpatients with bipolar mania for acute treatment. Symptom severity was assessed using the Young Mania Rating Scale (YMRS) at weeks 0, 1, 2, 3, and 4. Patients were included if they had had assessments at weeks 0 and 1 Remission was defined as an YMRS score ≤ 12. The Cox regression analysis was used to analyze factors associated with time to remission after 4 weeks of acute treatment. RESULTS: Four hundred and forty-nine patients entered the analysis. Seventy-one of the 449 subjects (15.8%) reached symptomatic remission within 4 weeks of acute treatment. Using forward multivariate Cox regression analysis, comorbid substance use disorders, earlier age at onset, and greater manic symptom severity at baseline found to be statistically significant predictors of a longer time to reach remission after 4 weeks of treatment. LIMITATIONS: As a retrospective chart review and naturalistic design, placebo effect and potentially confounding factors such as the possibility of missing records may have limited our results. CONCLUSIONS: Early identification and intervention with integrated therapy is considered to shorten time to remission for patients at high risk of poor treatment outcome. More studies are needed in other real-world settings to generalize our results.

Proliferation and apoptosis of T lymphocytes in patients with bipolar disorder.

The aim of the study was to evaluate proliferation capacity and susceptibility to apoptosis of T lymphocytes of patients with bipolar disorder (BD) and to investigate in vitro influence of two standard mood stabilizers: lithium and valproic acid on these parameters using flow cytometry. Our results show that T lymphocytes of BD patients, especially those treated with lithium, have reduced proliferation capacity compared to healthy people. In vitro studies showed that valproic acid reduces the number of cell divisions and percentages of proliferating cells regardless of health status but mainly in very high dose, while lithium has no significant influence on proliferation capacity of patients' T lymphocytes. Lymphocytes of BD patients are also more prone to apoptosis compared with healthy individuals which is related to high expression of Bax, a pro-apoptotic protein. In vitro lithium protected patients' lymphocytes from apoptosis proportionally to dose used. Valproic acid protected lymphocytes of patients from apoptosis mainly in therapeutic concentration. Our results show that mood stabilizers used to prevent relapses of the disease have anti-apoptotic effect on T lymphocytes of BD patients but they are not able to improve their proliferation capacity.

Adjunctive Bright Light Therapy for Bipolar Depression: A Randomized Double-Blind Placebo-Controlled Trial.

OBJECTIVE: Patients with bipolar disorder have recurrent major depression, residual mood symptoms, and limited treatment options. Building on promising pilot data, the authors conducted a 6-week randomized double-blind placebo-controlled trial to investigate the efficacy of adjunctive bright light therapy at midday for bipolar depression. The aims were to determine remission rate, depression symptom level, and rate of mood polarity switch, as well as to explore sleep quality. METHOD: The study enrolled depressed adults with bipolar I or II disorder who were receiving stable dosages of antimanic medication (excluding patients with hypomania or mania, mixed symptoms, or rapid cycling). Patients were randomly assigned to treatment with either 7,000-lux bright white light or 50-lux dim red placebo light (N=23 for each group). Symptoms were assessed weekly with the Structured Interview Guide for the Hamilton Depression Scale With Atypical Depression Supplement (SIGH-ADS), the Mania Rating Scale, and the Pittsburgh Sleep Quality Index. Remission was defined as having a SIGH-ADS score of 8 or less. RESULTS: At baseline, both groups had moderate depression and no hypomanic or manic symptoms. Compared with the placebo light group, the group treated with bright white light experienced a significantly higher remission rate (68.2% compared with 22.2%; adjusted odds ratio=12.6) at weeks 4-6 and significantly lower depression scores (9.2 [SD=6.6] compared with 14.9 [SD=9.2]; adjusted ß=-5.91) at the endpoint visit. No mood polarity switches were observed. Sleep quality improved in both groups and did not differ significantly between them. CONCLUSIONS: The data from this study provide robust evidence that supports the efficacy of midday bright light therapy for bipolar depression.

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.

Pharmacotherapy of mood disorders and psychosis in pre- and post-natal women.

INTRODUCTION: Untreated mood and psychotic disorders can have substantial adverse impacts on the patient, the fetus and the family, while treatment can ameliorate such problems. To address concerns by clinicians about the risks of psychotropic medications, this review addresses the risk/benefit analysis of somatic therapies for psychiatric disorders during pregnancy and lactation. Areas covered: All available research was reviewed on the impact on pregnancy and breastfeeding of mood and psychotic disorders, and of antidepressants, mood stabilizers, antipsychotic drugs, and electroconvulsive therapy. References cited in other reviews, case series, formal studies, pharmacologic discussions, and theoretical pieces were added. Available case control and other studies were critically reviewed and diverse explanations for their findings were considered. Expert opinion: The potential benefits of treatment of mood and psychotic disorders often outweigh the risks after alternative therapies have been considered. Some medications, particularly paroxetine and valproate, pose greater risks during pregnancy, while the teratogenic risks of lithium have probably been overstated. There is more experience with first than with second generation antipsychotic drugs during pregnancy and lactation. Nursing an infant is possible while taking a number of antidepressants, mood stabilizers or antipsychotic drugs.

Omega-3 Fatty Acids and Mood Stabilizers Alter Behavioural and Energy Metabolism Parameters in Animals Subjected to an Animal Model of Mania Induced by Fenproporex.

Studies have shown that changes in energy metabolism are involved in the pathophysiology of bipolar disorder (BD). It was suggested that omega-3 (ω3) fatty acids have beneficial properties in the central nervous system and that this fatty acid plays an important role in energy metabolism. Therefore, the study aimed to evaluate the effect of ω3 fatty acids alone and in combination with lithium (Li) or valproate (VPA) on behaviour and parameters of energy metabolism in an animal model of mania induced by fenproporex. Our results showed that co-administration of ω3 fatty acids and Li was able to prevent and reverse the increase in locomotor and exploratory activity induced by fenproporex. The combination of ω3 fatty acids with VPA was only able to prevent the fenproporex-induced hyperactivity. For the energy metabolism parameters, our results showed that the administration of Fen for the reversal or prevention protocol inhibited the activities of succinate dehydrogenase, complex II and complex IV in the hippocampus. However, hippocampal creatine kinase (CK) activity was decreased only for the reversal protocol. The ω3 fatty acids, alone and in combination with VPA or Li, prevented and reversed the decrease in complex II, IV and succinate dehydrogenase activity, whereas the decrease in CK activity was only reversed after the co-administration of ω3 fatty acids and VPA. In conclusion, our results showed that the ω3 fatty acids combined with VPA or Li were able to prevent and reverse manic-like hyperactivity and the inhibition of energy metabolism in the hippocampus, suggesting that ω3 fatty acids may play an important role in the modulation of behavioural parameters and energy metabolism.

Omega-3 fatty acids and mood stabilizers alter behavioral and oxidative stress parameters in animals subjected to fenproporex administration.

Studies have shown that oxidative stress is involved in the pathophysiology of bipolar disorder (BD). It is suggested that omega-3 (ω3) fatty acids are fundamental to maintaining the functional integrity of the central nervous system. The animal model used in this study displayed fenproporex-induced hyperactivity, a symptom similar to manic BD. Our results showed that the administration of fenproporex, in the prevent treatment protocol, increased lipid peroxidation in the prefrontal cortex (143%), hippocampus (58%) and striatum (181%), and ω3 fatty acids alone prevented this change in the prefrontal cortex and hippocampus, whereas the co-administration of ω3 fatty acids with VPA prevented the lipoperoxidation in all analyzed brain areas, and the co-administration of ω3 fatty acids with Li prevented this increase only in the prefrontal cortex and striatum. Moreover, superoxide dismutase (SOD) activity was decreased in the striatum (54%) in the prevention treatment, and the administration of ω3 fatty acids alone or in combination with Li and VPA partially prevented this inhibition. On the other hand, in the reversal treatment protocol, the administration of fenproporex increased carbonyl content in the prefrontal cortex (25%), hippocampus (114%) and striatum (91%), and in prefrontal coxter the administration of ω3 fatty acids alone or in combination with Li and VPA reversed this change, whereas in the hippocampus and striatum only ω3 fatty acids alone or in combination with VPA reversed this effect. Additionally, the administration of fenproporex resulted in a marked increase of TBARS in the hippocampus and striatum, and ω3 fatty acids alone or in combination with Li and VPA reversed this change. Finally, fenproporex administration decreased SOD activity in the prefrontal cortex (85%), hippocampus (52%) and striatum (76%), and the ω3 fatty acids in combination with VPA reversed this change in the prefrontal cortex and striatum, while the co-administration of ω3 fatty acids with Li reversed this inhibition in the hippocampus and striatum. In conclusion, our results support other studies showing the importance of ω3 fatty acids in the brain and the potential for these fatty acids to aid in the treatment of BD.

Trait-related alterations of N-acetylaspartate in euthymic bipolar patients: A longitudinal proton magnetic resonance spectroscopy study.

BACKGROUND: Neurochemical changes are responsible for bipolar disorder (BD) pathophysiology. Despite current progress in BD research, mood- and trait-related alterations in BD continue to elicit further investigation. METHODS: In this study, we report a longitudinal proton magnetic resonance spectroscopy study evaluating dorsomedial prefrontal cortex (DMPFC) metabolites N-acetylaspartate (NAA), creatine plus phosphocreatine (total creatine [tCr]), phosphorylcholine plus glycerophosphocholine, myo-inositol, and glutamate plus glutamine levels of manic and euthymic adult BD type I patients (n=48) treated with standard antimanic medicines, compared to matching healthy controls (n=44). RESULTS: DMPFC NAA values and NAA/tCr ratio were significantly lower in euthymic BD patients when compared with healthy controls with similar levels of other metabolites in all groups, indicating a trait-related NAA abnormality in euthymic BD patients. LIMITATIONS: of our study include a relatively low (1.5T) magnetic resonance field strength and variable drugs administered to achieve euthymia despite the best efforts to standardize the open fashion treatment. CONCLUSIONS: Our study contributes to the integrating models of trait-related metabolite alterations observed in euthymia since NAA is considered as a marker of neuronal viability and mitochondrial energy metabolism. In light of supporting and conflicting results reported previously, future studies with longitudinal designs and larger patient groups are warranted to better define both state- and trait-related cerebral metabolic alterations associated with BD pathophysiology.