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OBJECTIVE: Circadian rhythm disruption is commonly observed in bipolar disorder (BD). Daylight is the most powerful signal to entrain the human circadian clock system. This exploratory study investigated if solar insolation at the onset location was associated with the polarity of the first episode of BD I. Solar insolation is the amount of electromagnetic energy from the Sun striking a surface area of the Earth.METHODS: Data from 7488 patients with BD I were collected at 75 sites in 42 countries. The first episode occurred at 591 onset locations in 67 countries at a wide range of latitudes in both hemispheres. Solar insolation values were obtained for every onset location, and the ratio of the minimum mean monthly insolation to the maximum mean monthly insolation was calculated. This ratio is largest near the equator (with little change in solar insolation over the year), and smallest near the poles (where winter insolation is very small compared to summer insolation). This ratio also applies to tropical locations which may have a cloudy wet and clear dry season, rather than winter and summer.RESULTS: The larger the change in solar insolation throughout the year (smaller the ratio between the minimum monthly and maximum monthly values), the greater the likelihood the first episode polarity was depression. Other associated variables were being female and increasing percentage of gross domestic product spent on country health expenditures. (All coefficients: P ≤ 0.001).CONCLUSION: Increased awareness and research into circadian dysfunction throughout the course of BD is warranted.

Purpose Brief and effective screening measures are required to detect clinical depression in bipolar disorder (BD) patients. The purpose of this study was to demonstrate the clinical utility of a six-item, self-report Hamilton Depression Rating Scale (HAMD-6). Design and method Sixty BD outpatients completed questionnaires including the HAMD-6 before regular psychiatric appointments. Findings A 7+ HAMD-6 cut-off score correctly identified six of eight depressed patients, indicating 75% sensitivity and 84% specificity. Practice implications The results of this study suggest the HAMD-6 is an effective depression screening measure with BD patients living in the community. This brief self-report scale can be used in clinical settings to quickly identify those requiring more thorough clinical attention.

Purpose The BDSx (Bipolar Disorder Symptom Scale) is a brief self-report instrument designed for repeated measurement of bipolar disorder (BD) symptoms over time. Previous research indicates that the BDSx measures two depression (cognitive and somatic symptoms) and two hypo/mania factors (affrontive symptoms and elation/loss of insight). The purpose of this study was to validate BDSx responses relative to diagnoses of BD mood episodes. Methods Sixty BD outpatients attending routine clinic appointments completed the BDSx, the Hamilton Rating Scale for Depression, the Altman Self-Rating Mania Scale, and the Satisfaction with Life Scale. Blind to scale responses by patients, a clinic psychiatrist determined if patients were currently symptomatic. Results BDSx depression and hypo/mania subscales showed good construct validity vis-a-vis clinical diagnoses, and concurrent/discriminant validity with other self-report scales. And though not designed as a screening measure, sensitivity for the depression subscale is high at 88% (6+, 76% specificity), yet lower at 57% for the hypo/mania subscale (5+, 90% specificity). Conclusions The results of this study indicate that BDSx responses distinguish patients experiencing depressive and hypo/manic mood episodes. Findings support the psychometric properties of the Hebrew version of this scale. The BDSx enables those with bipolar disorder to monitor their symptoms, gauge symptom variability, and identify factors that proceed and sustain BD symptoms over time.

Olanzapine is a thienobenzodiazepine compound. It is one of the newer types of antipsychotic drugs used in the treatment of schizophrenia and other psychotic disorders. Several methods have been reported for analyzing olanzapine in its pure form or combined with other drugs and in biological fluids. These methods include high-performance liquid chromatography and liquid chromatography-tandem mass spectroscopy. Although many of the reported methods are accurate and sensitive, they require the use of sophisticated equipment, lack in situ analysis, and require expensive reagents. Moreover, several of these methods are cumbersome, require prolonged sample pretreatment, strict control of pH, and long reaction times. Here we present the development of a miniaturized electrochemical sensor that will enable minimally invasive, real-time, and in situ monitoring of olanzapine levels in microliter volumes of serum samples. For this purpose, we modified a microfabricated microelectrode with a platinum black film to increase the electrocatalytic activity of the microelectrode towards olanzapine oxidation; this improved the overall selectivity and sensitivity of the sensor. We observed in recorded voltammograms the anodic current dose response characteristics in microliter volumes of olanzapine-spiked serum samples that resulted in a limit of detection of 28.6 ± 1.3 nM and a sensitivity of 0.14 ± 0.02 µA/cm2 nM. Importantly, the platinum black-modified microelectrode exhibited a limit of detection that is below the clinical threshold (65–130 nM). Further miniaturizing and integrating such sensors into point-of-care devices provide real-time monitoring of olanzapine blood levels; this will enable treatment teams to receive feedback and administer adjustable olanzapine therapy.

Oxygen enriched air may increase oxygen pressure in brain tissue and have biochemical effects even in subjects without lung disease. Consistently, several studies demonstrated that normobaric oxygen treatment has clinical benefits in some neurological conditions. This study examined the efficacy of normobaric oxygen treatment in subjects with depression. In a randomized, double-blind trial, 55 participants aged 18–65 years with mild to moderate depression (had a Hamilton Rating Scale for Depression [HRSD] score of ≥ 8) were recruited to the study from the Southern district in Israel. Participants underwent a psychiatric inclusion assessment at baseline and then were randomly assigned to either normobaric oxygen treatment of 35% fraction of inspired oxygen or 21% fraction of inspired oxygen (room air) through a nasal tube, for 4 weeks, during the night. Evaluations were performed at baseline, 2 and 4 weeks after commencement of study interventions, using the following tools: HRSD; Clinical Global Impression (CGI) questionnaire; World Health Organization-5 questionnaire for the estimation of Quality of Life (WHO-5-QOL); Sense of Coherence (SOC) 13-item questionnaire; and, Sheehan Disability Scale (SDS). A multivariate regression analysis showed that the mean ± standard deviation [SD] changes in the HRSD scores from baseline to week four were − 4.2 ± 0.3 points in the oxygen-treated group and − 0.7 ± 0.6 in the control group, for a between-group difference of 3.5 points (95% confidence interval [CI] − 5.95 to − 1.0; P = 0.007). Similarly, at week four there was a between-group difference of 0.71 points in the CGI score (95% CI − 1.00 to − 0.29; P = 0.001). On the other hand, the analysis revealed that there were no significant differences in WHO-5-QOL, SOC-13 or SDS scores between the groups. This study showed a significant beneficial effect of oxygen treatment on some symptoms of depression.Trial registration: NCT02149563 (29/05/2014).

Introduction of old and new generations of antipsychotics leads to significant improvements in the positive symptoms of schizophrenia. However, negative symptoms remain refractory to conventional trials of antipsychotic therapy. Recently, there were several open clinical human trials with curcumin. Curcumin is a natural polyphenol, which has a variety of pharmacological activities, including antioxidative and neuroprotective effects. The studies showed that curcumin improved the negative symptoms of schizophrenia. The purpose of our study was to examine the efficacy of curcumin as an add-on agent to regular antipsychotic medications in patients with chronic schizophrenia.Thirty-eight patients with chronic schizophrenia were enrolled in a 24-week, double-blind, randomized, placebo-controlled study. The subjects were treated with either 3000 mg/d curcumin or placebo combined with antipsychotics from January 2015 to February 2017. The outcome measures were the Positive and Negative Symptoms Scale (PANSS) and the Calgary Depression Scale for Schizophrenia.Analysis of variance showed significant positive changes in both groups from baseline to the end of the study in all scales of measurement. There was a significant response to curcumin within 6 months in total PANSS (P = 0.02) and in the negative symptoms subscale (P = 0.04). There were no differences in the positive and general PANSS subscales, and the Calgary Depression Scale for Schizophrenia scores between the treatment and placebo groups. No patient complained of any adverse effect.The promising results of curcumin as an add-on to antipsychotics in the treatment of negative symptoms may open a new and safe therapeutic option for the management of schizophrenia. However, these results should be replicated in further studies.ClinicalTrials.gov Identifier: NCT02298985.

Schizophrenia (SCZ) is a chronic mental disorder that affects 23 million people worldwide. Clozapine (CLZ) is the most effective antipsychotic medication for treatment-resistant SCZ patients. Despite the superior efficacy of CLZ, it is dramatically underutilized due to the unavailable objective tests to measure CLZ efficacy. Several redox biomarkers in the blood have been correlated to CLZ efficacy. Yet, existing analytical methods change the levels of the molecules, their redox state, and eventually destroy the sample. By bridging the analytical gap and profiling the redox biomarkers, rapid and accurate CLZ treatment efficacy monitoring can be provided. Our overall goal is to develop a novel intelligent electrochemical biosensor based on an array of microelectrodes for CLZ treatment efficacy analysis. Here, we present the fabrication of the microelectrodes array, modification of the array with diffusion-limiting films, and characterization of the film’s effect on the generated electrochemical activity. The novelty of the biosensor lies within an array of microelectrodes modified with the positively charged biopolymer chitosan generating a set of complex electrochemical signals that are analyzed by using intelligent chemometric models. To achieve our goal, we microfabricated an array of 24 gold microelectrodes (100-µm-diameter working and 1,500-µm-diameter counter electrodes) by using photolithography and thin film deposition techniques. We used a 1.2% chitosan solution and applied cathodic current to electrodeposit thin films of chitosan onto the microelectrodes. To fabricate chitosan films with similar thicknesses and different densities, we measured the relationship between the thickness of the electrodeposited film and the applied electrodeposition current for 90s and 180s durations. A similar wet chitosan thickness (57.6±0.8 µm) was successfully achieved with 510 nA for 90s and 950 nA for 180s durations. Moreover, different dry chitosan thicknesses were obtained for 90s (10.7±0.1 µm) and 180s (13.2±0.6 µm) durations. Therefore, we calculated the porosity of the electrodeposited films as the ratio between the thicknesses of the wet and the dry films (5.38±0.09 and 4.36±0.20 at 510 nA for 90s and 950 nA for 180s, respectively). Furthermore, we used cyclic voltammetry to characterize the permeability of the modified films by measuring the ratio of the electrochemical signals generated from differently charged redox molecules (negatively charged ferrocyanide, neutral ferrocene, and positively charged hexaammineruthenium) before and after the modification. Statistical T-test analysis of the resulted permeabilities revealed significant differences for the charged molecules (P=0.85% for ferrocyanide; P=4.57% for hexaammineruthenium), while no significant difference was observed for the neutral molecule ferrocene. By providing a new way to analyze molecular profiles in blood, we anticipate establishing a new detection scheme for CLZ treatment efficacy that will help to transform schizophrenia management.

IntroductionSeveral studies of normobaric hyperoxia in some neurological conditions have demonstrated clinical benefits. Oxygen enriched air may increase oxygen pressure in brain tissue and have biochemical effects such as on brain erythropoietin gene expression, even in patients without lung disease.ObjectivesThis pilot, randomized, double-blind study examined the efficacy of normobaric hyperoxia as a treatment for depression.MethodsFifty-five consenting patients aged 18-65 years with mild to moderate depression were included in the study. Participants underwent a psychiatric inclusion assessment and a clinical evaluation by a psychiatric nurse at baseline, 2 and 4 weeks after commencement of study intervention. Participants were randomly assigned to normobaric hyperoxia of 35% fraction of inspired oxygen or 21% fraction of inspired oxygen (room air), through a nasal tube, for 4 weeks, during the night. Patients were rated blindly using the Hamilton Rating Scale for Depression (HRSD); Clinical Global Impression (CGI) questionnaire; Sheehan Disability Scale (SDS).Results The present study showed a significant improvement in HRSD (pConclusionsThis small pilot study showed a beneficial effect of normobaric hyperoxia on some symptoms of depression.DisclosureNo significant relationships.

Background Glycogen synthase kinase-3 (GSK-3) inhibition by lithium has been well established in vitro, but proof that this biochemical effect mediates lithium's beneficial action in patients with bipolar disorder is lacking. We studied whether lymphocyte GSK-3β activity measured indirectly in lithium- or valproate (VPA)-treated euthymic patients with bipolar disorder is different from controls. Methods Lymphocyte total and Ser-9-phospho-GSK-3β (inactive) levels were measured by Western blotting. Forty-seven patients with bipolar disorder and 32 age- and sex-matched control subjects were studied. Results No significant differences were found between lithium- and VPA-treated patients and controls in phospho-GSK-3β, total GSK-3β, or their ratio. Conclusions The data do not support the concept that in vivo, during chronic treatment of bipolar illness, GSK-3β is inhibited either by lithium or by VPA.

Pharmacological treatment of mental disorders is currently decided based on "trial and error" strategy. Mitochondrial multifaceted dysfunction is assumed to be a major factor in the pathophysiology and treatment of schizophrenia (SZ) and bipolar disorder (BD). This study aimed to explore the feasibility of using a profile of mitochondrial function parameters as a tool to predict the optimal drug for an individual patient (personalized medicine). Healthy controls (n = 40), SZ (n = 48) and BD (n = 27) patients were recruited. Mental and global state of the subjects, six mitochondrial respiration parameters and 14 mitochondrial function-related proteins were assessed in fresh lymphocytes following in-vitro or in-vivo treatment with five antipsychotic drugs and two mood-stabilizers. In healthy controls, hierarchal clustering shows a drug-specific effect profile on the different mitochondrial parameters following in-vitro exposure. Similar changes were observed in untreated SZ and BD patients with psychosis. Following a month of treatment of the latter patients, only responders showed a significant correlation between drug-induced in-vitro effect (prior to in-vivo treatment) and short-term in-vivo treatment effect for 45% of the parameters. Long- but not short-term psychotropic treatment normalized mitochondria-related parameters in patients with psychosis. Taken together, these data substantiate mitochondria as a target for psychotropic drugs and provide a proof of concept for selective mitochondrial function-related parameters as a predictive tool for an optimized psychotropic treatment in a given patient. This, however, needs to be repeated with an expanded sample size and additional mitochondria related parameters.

The BDSSixty BD outpatients attending routine clinic appointments completed the BDSBDSThe results of this study indicate that BDS

Simple logic would suggest that there should be some endophenotype for bipolar disorder. Possible endophenotypes could include specific variations in personality. Bagby and Ryder summarized the work up to that point by noting that the related personality traits of high neuroticism and harm avoidance seem to be associated with bipolar disorder as well as with unipolar depression, whereas higher novelty seeking may be associated only with bipolar patients. As these parameters are all very sensitive to the affective state, it is critical to examine the literature that pertains specifically to euthymic patients in order to evaluate the extent to which this signifies underlying personality (trait), and not primarily clinical status (state). Several important studies have been published since the Bagby and Ryder paper, which we review here. We restrict our current review to empirical studies which employed both adequate samples of euthymic (to minimize the state/trait dilemma) bipolar patients as well as healthy comparison subjects. This paper is restricted to frequently used explicit measures of personality - that is, self-report questionnaires: the Temperament and Character Inventory (TCI) based on Cloninger's psychobiological theory of temperament and character, the Revised NEO Personality Inventory based on the five-factor model of CostaMcCrae, and the Barratt Impulsiveness Scale (BIS-11) (23). No single dimension of 'personality' reviewed would qualify as a psychological marker for a bipolar disorder. Earlier findings as reviewed by Bagby and Ryder, of higher novelty seeking, were not replicated in these studies. Of the personality traits considered, the most promising candidate for marker or endophenotype would seem to be "impulsivity" as measured by the BIS-II.

In many international studies, rates of completed suicide and suicide attempts have a seasonal pattern that peaks in spring or summer. This exploratory study investigated the association between solar insolation and a history of suicide attempt in patients with bipolar I disorder. Solar insolation is the amount of electromagnetic energy from the Sun striking a surface area on Earth. Data were collected previously from 5536 patients with bipolar I disorder at 50 collection sites in 32 countries at a wide range of latitudes in both hemispheres. Suicide related data were available for 3365 patients from 310 onset locations in 51 countries. 1047 (31.1%) had a history of suicide attempt. There was a significant inverse association between a history of suicide attempt and the ratio of mean winter solar insolation/mean summer solar insolation. This ratio is smallest near the poles where the winter insolation is very small compared to the summer insolation. This ratio is largest near the equator where there is relatively little variation in the insolation over the year. Other variables in the model that were positively associated with suicide attempt were being female, a history of alcohol or substance abuse, and being in a younger birth cohort. Living in a country with a state-sponsored religion decreased the association. (All estimated coefficients p

Hypersalivation is a frequent, disturbing, and uncomfortable adverse effect of clozapine therapy that frequently leads to noncompliance. The aim of this study was to examine the efficacy of metoclopramide (dopamine D2 antagonist, antiemetic medication) as an option for management of hypersalivation associated with clozapine (HAC). A 3-week, double-blind, placebo-controlled trial was conducted in university-based research clinics from January 2012 to May 2014, on 58 inpatients treated with clozapine who were experiencing hypersalivation. The subjects were randomly divided into placebo and metoclopramide groups. The starting dose was 10 mg/d. Participants who did not respond were up-titrated 10 mg/d weekly to a total of 30 mg/d during the third week. The number of placebo capsules was increased accordingly up to 3 capsules per day. Primary outcome was the change from baseline to the end of study in the severity of hypersalivation as measured with the Nocturnal Hypersalivation Rating Scale and the Drooling Severity Scale. Secondary outcomes included Clinical Global Impression of Improvement scale and adverse effect scales. Significant improvement on the Nocturnal Hypersalivation Rating Scale was demonstrated in the metoclopramide group from the end of the second week (P < 0.004), and on the Drooling Severity Scale (P < 0.02) in the third week. Clinical Global Impression-Improvement scale scores revealed major improvement. Twenty subjects (66.7%) treated with metoclopramide reported significant decline or total disappearance of HAC in comparison to 8 patients (28.6%) who received placebo (P = 0.031). No adverse effects to metoclopramide were reported. Metoclopramide was found to be safe and effective for the treatment of HAC.

BACKGROUND: Peer support is an established component of recovery from bipolar disorder, and online support groups may offer opportunities to expand the use of peer support at the patient's convenience. Prior research in bipolar disorder has reported value from online support groups.AIMS: To understand the use of online support groups by patients with bipolar disorder as part of a larger project about information seeking.METHODS: The results are based on a one-time, paper-based anonymous survey about information seeking by patients with bipolar disorder, which was translated into 12 languages. The survey was completed between March 2014 and January 2016 and included questions on the use of online support groups. All patients were diagnosed by a psychiatrist. Analysis included descriptive statistics and general estimating equations to account for correlated data.RESULTS AND CONCLUSIONS: The survey was completed by 1222 patients in 17 countries. The patients used the Internet at a percentage similar to the general public. Of the Internet users who looked online for information about bipolar disorder, only 21.0% read or participated in support groups, chats, or forums for bipolar disorder (12.8% of the total sample). Given the benefits reported in prior research, clarification of the role of online support groups in bipolar disorder is needed. With only a minority of patients using online support groups, there are analytical challenges for future studies.

Information seeking is an important coping mechanism for dealing with chronic illness. Despite a growing number of mental health websites, there is little understanding of how patients with bipolar disorder use the Internet to seek information.A 39 question, paper-based, anonymous survey, translated into 12 languages, was completed by 1222 patients in 17 countries as a convenience sample between March 2014 and January 2016. All patients had a diagnosis of bipolar disorder from a psychiatrist. Data were analyzed using descriptive statistics and generalized estimating equations to account for correlated data.976 (81 % of 1212 valid responses) of the patients used the Internet, and of these 750 (77 %) looked for information on bipolar disorder. When looking online for information, 89 % used a computer rather than a smartphone, and 79 % started with a general search engine. The primary reasons for searching were drug side effects (51 %), to learn anonymously (43 %), and for help coping (39 %). About 1/3 rated their search skills as expert, and 2/3 as basic or intermediate. 59 % preferred a website on mental illness and 33 % preferred Wikipedia. Only 20 % read or participated in online support groups. Most patients (62 %) searched a couple times a year. Online information seeking helped about 2/3 to cope (41 % of the entire sample). About 2/3 did not discuss Internet findings with their doctor.Online information seeking helps many patients to cope although alternative information sources remain important. Most patients do not discuss Internet findings with their doctor, and concern remains about the quality of online information especially related to prescription drugs. Patients may not rate search skills accurately, and may not understand limitations of online privacy. More patient education about online information searching is needed and physicians should recommend a few high quality websites.

OBJECTIVE: To confirm prior findings that the larger the maximum monthly increase in solar insolation in springtime, the younger the age of onset of bipolar disorder.METHOD: Data were collected from 5536 patients at 50 sites in 32 countries on six continents. Onset occurred at 456 locations in 57 countries. Variables included solar insolation, birth-cohort, family history, polarity of first episode and country physician density.RESULTS: There was a significant, inverse association between the maximum monthly increase in solar insolation at the onset location, and the age of onset. This effect was reduced in those without a family history of mood disorders and with a first episode of mania rather than depression. The maximum monthly increase occurred in springtime. The youngest birth-cohort had the youngest age of onset. All prior relationships were confirmed using both the entire sample, and only the youngest birth-cohort (all estimated coefficients P < 0.001).CONCLUSION: A large increase in springtime solar insolation may impact the onset of bipolar disorder, especially with a family history of mood disorders. Recent societal changes that affect light exposure (LED lighting, mobile devices backlit with LEDs) may influence adaptability to a springtime circadian challenge.

There is considerable international interest in online education of patients with bipolar disorder, yet little understanding of how patients use the Internet and other sources to seek information. 1171 patients with a diagnosis of bipolar disorder in 17 countries completed a paper-based, anonymous survey. 81% of the patients used the Internet, a percentage similar to the general public. Older age, less education, and challenges in country telecommunications infrastructure and demographics decreased the odds of using the Internet. About 78% of the Internet users looked online for information on bipolar disorder or 63% of the total sample. More years of education in relation to the country mean, and feeling very confident about managing life decreased the odds of seeking information on bipolar disorder online, while having attended support groups increased the odds. Patients who looked online for information on bipolar disorder consulted medical professionals plus a mean of 2.3 other information sources such as books, physician handouts, and others with bipolar disorder. Patients not using the Internet consulted medical professionals plus a mean of 1.6 other information sources. The percentage of patients with bipolar disorder who use the Internet is about the same as the general public. Other information sources remain important.

Background Information seeking is an important coping mechanism for dealing with chronic illness. Despite a growing number of mental health websites, there is little understanding of how patients with bipolar disorder use the Internet to seek information. Methods A 39 question, paper-based, anonymous survey, translated into 12 languages, was completed by 1222 patients in 17 countries as a convenience sample between March 2014 and January 2016. All patients had a diagnosis of bipolar disorder from a psychiatrist. Data were analyzed using descriptive statistics and generalized estimating equations to account for correlated data. Results 976 (81 % of 1212 valid responses) of the patients used the Internet, and of these 750 (77 %) looked for information on bipolar disorder. When looking online for information, 89 % used a computer rather than a smartphone, and 79 % started with a general search engine. The primary reasons for searching were drug side effects (51 %), to learn anonymously (43 %), and for help coping (39 %). About 1/3 rated their search skills as expert, and 2/3 as basic or intermediate. 59 % preferred a website on mental illness and 33 % preferred Wikipedia. Only 20 % read or participated in online support groups. Most patients (62 %) searched a couple times a year. Online information seeking helped about 2/3 to cope (41 % of the entire sample). About 2/3 did not discuss Internet findings with their doctor. Conclusion Online information seeking helps many patients to cope although alternative information sources remain important. Most patients do not discuss Internet findings with their doctor, and concern remains about the quality of online information especially related to prescription drugs. Patients may not rate search skills accurately, and may not understand limitations of online privacy. More patient education about online information searching is needed and physicians should recommend a few high quality websites. Electronic supplementary material The online version of this article (doi:10.1186/s40345-016-0058-0) contains supplementary material, which is available to authorized users.

Bipolar-disorder (manic-depressive illness) is a severe chronic illness affecting ∼1% of the adult population. It is treated with mood-stabilizers, the prototypic one being lithium-salts (lithium), but it has life threatening side-effects and a significant number of patients fail to respond. The lithium-inhibitable enzyme inositol-monophosphatase (IMPase) is one of the viable targets for lithium's mechanism of action. Calbindin-D28k (calbindin) up-regulates IMPase activity. The IMPase-calbindincomplex was modeled using the program MolFit. The in-silico model indicated that the 55-66 amino-acid segment of IMPase anchors calbindin via Lys59 and Lys61 with a glutamate in between (Lys-Glu-Lys motif) and that the motif interacts with residues Asp24 and Asp26 of calbindin. We found that differently from wildtype calbindin, IMPase was not activated by mutated calbindin in which Asp24 and Asp26 were replaced by alanine. Calbindin's effect was significantly reduced by a linear peptide with the sequence of amino acids 58-63 of IMPase (peptide 1) and by six amino-acid linear peptides including at least part of the Lys-Glu-Lys motif. The three amino-acid peptide Lys-Glu-Lys or five amino-acid linear peptides containing this motif were ineffective. Mice administered peptide 1 intracerebroventricularly exhibited a significant anti-depressant-like reduced immobility in the forced-swim test. Based on the sequence of peptide 1, and to potentially increase the peptide's stability, cyclic and linear pre-cyclic analog peptides were synthesized. One cyclic peptide and one linear pre-cyclic analog peptide inhibited calbindin-activated brain IMPase activity in-vitro. Our findings may lead to the development of molecules capable of inhibiting IMPase activity at an alternative site than that of lithium.

The inositol-depletion hypothesis proposes that lithium attenuates phosphatidylinositol signaling. Knockout (KO) mice of two genes (IMPA1 or Slc5a3), each encoding for a protein related to inositol metabolism, were studied in comparison with lithium-treated mice. Since we previously demonstrated that these KO mice exhibit a lithium-like neurochemical and behavioral phenotype, here we searched for pathways that may mediate lithium's/the KO effects. We performed a DNA-microarray study searching for pathways affected both by chronic lithium treatment and by the KO of each of the genes. The data were analyzed using three different bioinformatics approaches. We found upregulation of mitochondria-related genes in frontal cortex of lithium-treated, IMPA1 and Slc5a3 KO mice. Three out of seven genes differentially expressed in all three models, Cox5a, Ndufs7, and Ndufab, all members of the mitochondrial electron transfer chain, have previously been associated with bipolar disorder and/or lithium treatment. Upregulation of the expression of these genes was verified by real-time PCR. To further support the link between mitochondrial function and lithium's effect on behavior, we determined the capacity of chronic low-dose rotenone, a mitochondrial respiratory chain complex I inhibitor, to alter lithium-induced behavior as measured by the forced-swim and the amphetamine-induced hyperlocomotion paradigms. Rontenone treatment counteracted lithium's effect on behavior, supporting the proposition suggested by the bioinformatics analysis for a mitochondrial function involvement in behavioral effects of lithium mediated by inositol metabolism alterations.The results provide support for the notion that mitochondrial dysfunction is linked to bipolar disorder and can be ameliorated by lithium. The phenotypic similarities between lithium-treated wild-type mice and the two KO models suggest that lithium may affect behavior by altering inositol metabolism.

Objectives Depression is a widespread mental disorder in which nearly half of the affected people have recurrent symptoms. Drug combinations may produce cumulative adverse effects, especially in elderly and physically ill patients. It was demonstrated that curcumin possesses antidepressive activity in various animal models of depression, and a combination of curcumin with some antidepressants potentiates the antidepressive effect of these agents. We sought to evaluate the efficacy of curcumin as an antidepressive agent in a combination with other antidepressants in patients with major depression. Methods Forty patients with a first episode of depression participated in a 5-week, double-blind, randomized, placebo-controlled study. The subjects were treated with either 500-mg/d curcumin or placebo together with antidepressants (escitalopram or venlafaxine) during August 2010 until June 2011. The outcome measures were Clinical Global Impression-Severity Scale, Hamilton Depression Rating Scale, and Montgomery-Asberg Depression Rating Scale. Results Analysis of variance showed significant positive changes in both groups from baseline to the end of the study in all scales of measurement. These changes became significant from the first visit after 7 days of treatment. There was no difference between curcumin and placebo, which means negative results. However, the patients in the curcumin group demonstrated a trend to a more rapid relief of depressive symptoms in comparison to those in the placebo group. None of the patients complained of any adverse effect during the study. Conclusions Although there is no definitive proof that curcumin can induce an earlier beneficial effect of antidepressive agents, it seems like an extended study is needed to prove it, using higher therapeutic doses of curcumin.

Lithium has been a standard pharmacological treatment for bipolar disorder over the last 60 years; however, the molecular targets through which lithium exerts its therapeutic effects are still not defined. Attenuation of the phosphatidylinositol signal transduction pathway as a consequence of inhibition of inositol monophosphatase (IMPase) has been proposed as one of the possible mechanisms for lithium-induced mood stabilization.The objective was to study the behavioral effect of the specific competitive IMPase inhibitor L-690,330 in mice in the lithium-sensitive pilocarpine-induced seizures paradigm and the forced swim test (FST).The inhibitor was administered intracerebroventricularly in liposomes.L-690,330 increased the sensitivity to subconvulsive doses of pilocarpine and decreased immobility time in the FST.It is possible that the behavioral effects of lithium in the pilocarpine-induced seizures and in the FST are mediated through the inhibition of IMPase, but reversal of the inhibitor's effect with intracerebroventricular inositol would be an important further step in proof.

Background:Eicosapentaenoic acid (EPA) is one of the major components of fish oils. Omega-3 fatty acids, particularly EPA, have been hypothesized to play a role in the etiology, pathogenesis and treatment of mood disorders. Clinical studies have shown beneficial effects of omega-3 fatty acids in major depression, bipolar disorder and other psychiatric disorders.Objective:The present study design evaluates the effect of EPA in the Porsolt forced swimming test.Results:EPA alone did not reduce the immobility time and did not enhance the anti-immobility effect of a low dose of imipramine. Contrary to the hypothesis, EPA slightly increased the immobility time, and in some experiments tended to reduce the anti-despair effect of imipramine.Conclusion:The present results do not provide an animal model for the antidepressant effect of EPA as demonstrated in clinical experiments. The mechanism of EPA antidepressant action is unknown and the Porsolt forced swimming test could be non-sensitive for its antidepressant properties.

Additional file 1. Questionnaire: Information seeking in bipolar disorder.

Several studies of normobaric hyperoxia in neurological conditions have found positive results. The impaired energy metabolism due to mitochondrial dysfunction and frontal lobe hypofunction in schizophrenia might be improved by increasing O2 supply to the brain. Normobaric hyperoxia may be a potential treatment for schizophrenia. Participants in this study, outpatients with chronic schizophrenia and inhabitants of community-based psychiatric institutions (hostels), underwent baseline psychiatric/cognitive assessment and were randomly assigned to either a treatment intervention of oxygen-enriched air inhalation (normobaric hyperoxia of 40% fraction of inspired oxygen) or regular air inhalation (21% fraction of inspired oxygen), through a nasal tube, for 4 weeks. Patients were given the air/oxygen inhalations during the night (mainly while sleeping) for at least 7 hours a night. After completing 4 weeks of treatment, patients were switched (crossed over) to the other treatment intervention. Fifteen patients completed the entire study. Five additional patients completed phase A only. There was significant improvement in total Positive and Negative Symptoms Scale score of patients who received oxygen compared with the control group. There were positive effects of oxygen on memory and attention in neuropsychological performance tests. The effect size is small despite the statistical significance, but the patient group was extremely chronic and severely impaired. These results are a proof of concept, and normobaric hyperoxia should be studied in patients with milder forms of the illness and earlier in the course of illness.

Bersudsky Y, Applebaum J, Gaiduk Y, Sharony L, Mishory A, Podberezsky A, Agam G, Belmaker RH. Valnoctamide as a valproate substitute with low teratogenic potential in mania: a double-blind, controlled, add-on clinical trial. Bipolar Disord 2010: 12: 376–382. © 2010 The Authors. Journal compilation © 2010 John Wiley & Sons A/S. Objectives: Valproic acid’s well-known teratogenicity limits its use in women of childbearing age. Valnoctamide is an analog of valproate that does not undergo biotransformation to the corresponding free acid. In mice, valnoctamide has been shown to be distinctly less teratogenic than valproate. Valnoctamide is an anticonvulsant, and we hypothesized that valnoctamide is antimanic. Methods: We performed a double-blind, five-week, add-on, controlled trial of valnoctamide in mania. Patients were treated with risperidone at doses of the physician’s discretion. Valnoctamide or placebo was begun at doses of 600 mg/day and increased to 1200 mg after four days. Weekly ratings by a psychiatrist blind to the study drug were conducted using the Brief Psychiatric Rating Scale (BPRS), the Young Mania Rating Scale (YMRS), and the Clinical Global Impression (CGI). Results: Fifteen valnoctamide patients and 17 placebo patients completed at least one post-baseline week and were included in data analysis. In all efficacy measures valnoctamide was more effective than placebo as an add-on to risperidone, using two-way analysis of variance (ANOVA) with time as the within-subject factor. Two-way ANOVA showed a significant effect of time (p

Objectives: Lithium, valproate, and carbamazepine decrease stimulated brain cyclic-AMP (cAMP) levels. Adenylyl cyclase (AC), of which there are nine membrane-bound isoforms (AC1-AC9), catalyzes the formation of cAMP. We have recently demonstrated preferential inhibition of AC5 by lithium. We now sought to determine whether carbamazepine and valproate also preferentially inhibit specific AC isoforms or decrease cAMP levels via different mechanisms. Methods: COS7 cells were transfected with one of AC1-AC9, with or without D1-dopamine receptors. Carbamazepine’s and valproate’s effect on forskolin- or D1 agonist-stimulated ACs was studied. The effect of Mg2+ on lithium’s inhibition was studied in membrane-enriched fraction from COS7 cells co-expressing AC5 and D1 receptors. AC5 knockout mice were tested for a behavioral phenotype similar to that of lithium treatment. Results: Carbamazepine preferentially inhibited forskolin-stimulated AC5 and AC1 and all D1 agonist-stimulated ACs, with AC5 and AC7 being the most sensitive. When compared to 1 or 3 mM Mg2+, 10 mM Mg2+ reduced lithium-induced AC5 inhibition by 70%. In silico modeling suggests that among AC isoforms carbamazepine preferentially affects AC1 and AC5 by interacting with the catechol-estrogen site. Valproate did not affect any forskolin- or D1 receptor-stimulated AC. AC5 knockout mice responded similarly to antidepressant- or lithium-treated wild-types in the forced-swim test but not in the amphetamine-induced hyperactivity mania model. Conclusions: Lithium and carbamazepine preferentially inhibit AC5, albeit via different mechanisms. Lithium competes with Mg2+, which is essential for AC activity; carbamazepine competes for AC’s catechol-estrogen site. Antidepressant-like behavior of AC5 knockout mice in the forced-swim test supports the notion that AC5 inhibition is involved in the antidepressant effect of lithium and carbamazepine. The effect of lithium and carbamazepine to lower cAMP formation in AC5-rich dopaminergic brain regions suggests that D1-dopamine receptors in these regions are involved in the antidepressant effect of mood stabilizers.

Background Bipolar disorder is a complex disorder hypothesized to involve an interaction of multiple susceptibility genes and environmental factors. The environmental factors may be mediated via epigenetic mechanisms such as DNA methylation. Since a different extent of DNA methylation has recently been reported in lymphoblastoid cells derived from monozygotic twins discordant for bipolar disorder, we hypothesized that bipolar patients exhibit a different extent of leukocyte global DNA methylation compared with healthy controls. Methods DNA was extracted from peripheral blood leukocytes of 49 euthymic bipolar patients and 27 matched healthy controls. Percent of global genome DNA methylation was measured using the cytosine-extension method. Plasma homocysteine levels were measured by HPLC. Results Leukocyte global DNA methylation did not differ between bipolar patients [62.3% ± 18.0 (S.D)] and control subjects (63.9% ± 14.6), p = 0.70. Bipolar patients' plasma homocysteine levels (11.5 µM ± 4.8) did not differ from those of healthy controls (11.4 ± 2.9), p = 0.92. Limitations The assay we used, based on restriction by methylation-sensitive/insensitive enzymes followed by a radioactive DNA polymerase reaction was approved to accurately measure global DNA methylation, but has technical limitations i.e. restriction enzymes do not cleave all potential methylation sites in the genome and restriction sites may be altered by mutations or polymorphisms. Conclusions The lack of difference in leukocyte global DNA methylation between euthymic bipolar patients and healthy controls does not rule out the possibility that altered methylation of specific promoter regions is involved in the etiology of the disorder.

Objective: Lithium inhibits inositol monophosphatase and also reduces inositol transporter function. To determine if one or more of these mechanisms might underlie the behavioral effects of lithium, we studied inositol transporter knockout mice. We previously reported that heterozygous knockout mice with reduction of 15–37% in brain inositol had no abnormalities of pilocarpine sensitivity or antidepressant-like behavior in the Porsolt forced swim test. We now report on studies of homozygous inositol transporter knockout mice. Methods: Homozygote knockout mice were rescued by 2% inositol supplementation to the drinking water of the dam mice through pregnancy and lactation. Genotyping was carried out by polymerase chain reaction followed by agarose electrophoresis. Brain free myo-inositol levels were determined gas-chromatographically. Motor activity and coordination were assessed by the rotarod test. Behavior of the mice was studied in lithium–pilocarpine seizure models for lithium action and in the Porsolt forced swim test model for depression. Results: In homozygote knockout mice, free inositol levels were reduced by 55% in the frontal cortex and by 60% in the hippocampus. There were no differences in weight or motor coordination by the rotarod test. They behaved similarly to lithium-treated animals in the model of pilocarpine seizures and in the Porsolt forced swimming test model of depression. Conclusions: Reduction of brain inositol more than 15–37% may be required to elicit lithium-like neurobehavioral effects.

In mice glycogen synthase kinase (GSK)-3beta heterozygote knockout status was reported to cause reduced immobility in the Porsolt forced swim test and reduced amphetamine-induced hyperactivity, behaviors that mimic the effects of lithium. GSK-3beta protein and mRNA level and activity have been reported to be reduced in the postmortem brain of schizophrenia patients and this could suggest the involvement of GSK-3beta in the etiology of schizophrenia. However, apomorphine-induced stereotyping was reported to be unchanged in GSK-3beta heterozygote (HZ) knockout (KO) mice. As such behaviors are not always robust, study in another laboratory seemed indicated. Motor activity and coordination were assessed in the rotarod test. Behavior was studied in the following tests: pilocarpine-induced seizures model for lithium action, Porsolt forced swim test, tail suspension test, elevated plus-maze, large open field, startle response and prepulse inhibition of acoustic startle response, amphetamine-induced hyperactivity, and apomorphine-induced stereotypic climbing. We could not confirm the report that GSK-3beta HZ KO mice exhibit reduced immobility in the Porsolt forced swim or reduced amphetamine-induced hyperactivity in a manner mimicking the behavioral effects of lithium. We did not find increased apomorphine-induced stereotypic climbing or disruption of prepulse inhibition, suggesting that human postmortem findings regarding GSK-3beta in schizophrenia are not mediated by changes in dopamine receptors and are not the cause of prepulse inhibition deficits in schizophrenia. These data do not support the role of GSK-3beta in schizophrenia or in the mechanism of therapeutic action of lithium. Although differences in the genetic background of the GSK-3beta HZ KOs used in the present study compared with that of the previous study could be responsible, such results could suggest that the previously reported effects of GSK-3beta knockout on behavior are not robust.

Electroconvulsive therapy (ECT) involves the induction of a generalized tonic–clonic seizure by means of an electric current applied to the head of the patient. The procedure is performed under general anesthesia with the use of muscle relaxants. The efficacy and safety of ECT has been controversial since the introduction of this treatment in the 1930s. Today, ECT is considered to be a safe and effective therapeutic option in treating a number of psychiatric illnesses. With recent technical advances, ECT has fewer adverse results, is safer even in the very old and is effective for a wider range of indications. Nevertheless, many physicians remain hesitant to refer their patients for ECT because of the mistaken belief that this form of treatment is primitive and barbaric. In this article, we review the use of ECT in the elderly.

Background We have previously reported that homocysteine levels are elevated in euthymic bipolar patients with functional deterioration. The current study was designed to extend this finding by examining the relationship between neuropsychological functioning and homocysteine levels in euthymic bipolar patients. Methods Fifty-seven euthymic bipolar outpatients were assessed for serum levels of homocysteine, folic acid, and vitamin B-12 and administered a battery of neuropsychological tests. Results We found that male bipolar subjects showed higher average homocysteine levels than a comparison group of normal subjects, that poorer functioning on a task of executive function (Wisconsin Card Sort) was related to higher homocysteine levels, and that folic acid or vitamin B-12 levels did not significantly affect neuropsychological functioning. Limitations These results, while suggesting some relationship between higher homocysteine levels, bipolar illness, and impairment in cognitive function do not establish any causative effects. Conclusions The findings of this study confirm that in euthymic bipolar patients, higher homocysteine levels are associated with poorer performance in some neuropsychological tests. Treatment trials will be required before it will be known if the putative decrements in the executive function of bipolar patients can be reversed, or at least retarded, if homocysteine levels are reduced (as, for example, by dietary addition of B vitamin supplements).

Objectives: Rapid reduction of up to 80% in plasma tryptophan level can be accomplished by administering an oral tryptophan-free amino acid solution, which induces hepatic protein synthesis and thereby depletes available plasma tryptophan. Rapid tryptophan depletion (RTD) has been shown to induce transient depressive symptoms in patients with remitted major depression. The effect of RTD in acutely manic patients has not been studied. Methods: We carried out a double-blind, placebo-controlled pilot study of RTD in acutely manic patients. Patients were randomized to the treatment groups. Sodium valproate treatment was started at a dose of 1000 mg/day and continued throughout the 7-day study. On days 1-7, patients received a daily tryptophan-free amino acid drink or a placebo drink. The tryptophan-free amino acid drink contained a mix of amino acids without tryptophan. The placebo drink contained the additives and constituents of the real mixture to provide identical flavor and texture without the amino acids. Ratings were administered at baseline and then repeated on days 3, 5, and 7. All ratings were carried out by an experienced rater who was blind to the group assignment of patients. Results: A total of 23 patients entered the study and 17 completed the 7-day treatment protocol. The patients who received the amino acid drink showed greater improvement in mania ratings. The differences in Young Mania Rating Scale (YMRS) and Clinical Global Impression (GCI) scores were significant. However, the intolerance rate was high (23%) and the findings in this pilot study are based only on results from those patients who were able to tolerate the drink. Conclusions: Rapid tryptophan depletion may have an antimanic effect.

The search for psychological markers or for psychological endophenotypes for bipolar affective disorder has been frustrating, and the study of neuropsychological and neurocognitive functioning may be useful in this search. This article presents the results of a study comparing Rorschach protocols from a sample of adult euthymic bipolar patients (N = 18) and matched healthy controls (N = 8). Bipolar patients showed a higher proportion of immature responses and more instances of thought disorder; patients also showed significantly more severe thought disorder. These findings are discussed in the context of 2 related previous studies. We suggest that our modest series of studies using the Rorschach Inkblot Test provides preliminary evidence that certain variables-especially the measures of thought disorder but possibly also the lack of emotional responses under cognitive "control" and the excessive proportion of immature content responses-may represent a possible endophenotype of bipolar disorder.

Lithium has been the standard pharmacological treatment for bipolar disorder over the last 50 years; however, the molecular targets through which lithium exerts its therapeutic effects are still not defined. We characterized the phenotype of mice with a dysfunctional IMPA1 gene (IMPA1-/-) to study the in vivo physiological functions of IMPA1, in general, and more specifically its potential role as a molecular target in mediating lithium-dependent physiological effects. Homozygote IMPA1-/- mice died in utero between days 9.5 and 10.5 post coitum (p.c.) demonstrating the importance of IMPA1 in early embryonic development. Intriguingly, the embryonic lethality could be reversed by myo-inositol supplementation via the pregnant mothers. In brains of adult IMPA1-/- mice, IMPase activity levels were found to be reduced (up to 65% in hippocampus); however, inositol levels were not found to be altered. Behavioral analysis of the IMPA1-/- mice indicated an increased motor activity in both the open-field test and the forced-swim test as well as a strongly increased sensitivity to pilocarpine-induced seizures, the latter supporting the idea that IMPA1 represents a physiologically relevant target for lithium. In conclusion the IMPA1-/- mouse represents a novel model to study inositol homeostasis, and indicates that genetic inactivation of IMPA1 can mimic some actions of lithium.

Objectives Patients with bipolar disorder are characterized by an unusually high divorce rate. As such, the purpose of the present study was to uncover information relating specifically to the impact of bipolar disorder on patients and spouses individually, and on the marital relationship from the perspectives of both patients and spouses. Methods Eleven patients with bipolar disorder and ten spouses were interviewed separately about the impact of bipolar disorder on their lives and on their marital relationship. Data were analyzed using the grounded theory method. Results The impact of bipolar disorder for spouses included self-sacrifice, caregiving burden, emotional impact, and a sense of personal evolution. The impact of bipolar disorder on patients included an emotional impact, responsibility for self-care, and struggling socially and developmentally. When comparing patient and spouse perspectives on the impact of the disorder, neither the patient nor the spouse was able to accurately assess the impact of the disorder on their partner's lives. The impact of bipolar disorder on the relationship included volatility in the relationship, strengthening the relationship, weakening the relationship, and family planning. Conclusions The research indicated that patients and partners alike struggle with the tremendous impact of bipolar disorder on their lives and on their relationships. Given the high rates of divorce and volatility in these relationships, healthcare professionals can provide (or refer to) emotional and practical support both to patients and spouses on their own, and as a couple in their clinics.

Reports of toxic effects on the kidney of lithium treatment emerged very soon after lithium therapy was introduced. Lithium-induced nephrogenic diabetes insipidus is usually self-limiting or not clinically dangerous. Some reports of irreversible chronic kidney disease and renal failure were difficult to attribute to lithium treatment since chronic kidney disease and renal failure exist in the population at large. In recent years, large-scale epidemiological studies have convincingly shown that lithium treatment elevates the risk of chronic kidney disease and renal failure. Most patients do not experience renal side effects. The most common side effect of polyuria only weakly predicts increasing creatinine or reduced kidney function. Among those patients who do experience decrease in creatinine clearance, some may require continuation of lithium treatment even as their creatinine increases. Other patients may be able to switch to a different mood stabilizer medication, but kidney function may continue to deteriorate even after lithium cessation. Most, but not all, evidence today recommends using a lower lithium plasma level target for long-term maintenance and thereby reducing risks of severe nephrotoxicity.

The effects of creatine on brain metabolism and the potential cognitive enhancing properties of this compound raise the possibility of developing a new augmentation therapeutic strategy in schizophrenia especially in patients demonstrating negative and cognitive symptomatology.Seven inpatients with chronic schizophrenia presenting with treatment resistant negative symptoms were enrolled into exploratory treatment study with creatine monohydrate augmentation at a daily high-dose of 10 grams, administered for 6 months. Several clinical rating scales and a computerized cognitive assessment battery were applied.Creatine treatment mildly improved the schizophrenia symptomatology but there were no significant changes in cognitive functions. Several ward behaviors were also improved. Tardive parkinsonism improved numerically by above 40% in 4 out of 6 patients.This small, open design study of high dose creatine add-on for 6 months in chronic inpatients with schizophrenia demonstrated only mild positive effects on the patients' symptomatology and behavior and might have beneficial effect on tardive parkinsonism.

Purpose:Two common approaches to identify subgroups of patients with bipolar disorder are clustering methodology (mixture analysis) based on the age of onset, and a birth cohort analysis. This study investigates if a birth cohort effect will influence the results of clustering on the age of onset, using a large, international database.Methods:The database includes 4037 patients with a diagnosis of bipolar I disorder, previously collected at 36 collection sites in 23 countries. Generalized estimating equations (GEE) were used to adjust the data for country median age, and in some models, birth cohort. Model-based clustering (mixture analysis) was then performed on the age of onset data using the residuals. Clinical variables in subgroups were compared.Results:There was a strong birth cohort effect. Without adjusting for the birth cohort, three subgroups were found by clustering. After adjusting for the birth cohort or when considering only those born after 1959, two subgroups were found. With results of either two or three subgroups, the youngest subgroup was more likely to have a family history of mood disorders and a first episode with depressed polarity. However, without adjusting for birth cohort (three subgroups), family history and polarity of the first episode could not be distinguished between the middle and oldest subgroups.Conclusion:These results using international data confirm prior findings using single country data, that there are subgroups of bipolar I disorder based on the age of onset, and that there is a birth cohort effect. Including the birth cohort adjustment altered the number and characteristics of subgroups detected when clustering by age of onset. Further investigation is needed to determine if combining both approaches will identify subgroups that are more useful for research.

ADAM (A Disintegrin And Metalloprotease)12 is a member of a family of integral membrane and secreted glycoproteins. ADAM12 has recently been detected in urine. In the present study we measured ADAM12 protein levels in urine from bipolar patients vs. healthy controls. Nineteen bipolar patients and 22 matched-control subjects were studied. Urine samples were concentrated and Western-blot analysis used to determine ADAM12 protein levels. The 92 kDa form of urine ADAM12 protein levels were highly elevated in Li-treated bipolar patients compared with normal controls. The 68 kDa form of urine ADAM12 protein levels did not differ. Future experiments are needed to explore a potential link between ADAM12 protein level elevation and lithium response.

Two leading hypotheses to explain lithium action in bipolar disorder propose either inositol depletion or inhibition of GSK-3 as mechanisms of action. Behavioral effects of lithium are mimicked in Gsk-3β +/− mice, but the contribution of inositol depletion to these behaviors has not been tested. According to the inositol depletion hypothesis, lithium-sensitive behavior is secondary to impaired phosphatidylinositol synthesis caused by inositol deficiency. By disrupting the sodium myo-inositol transporter1 gene, SMIT1 , we show that depletion of brain myo-inositol in SMIT1 +/− mice has no effect on lithium-sensitive behavior. These findings, taken together with our previous work showing that SMIT −/− mice have an even greater depletion of inositol in brain with no reduction in phosphatidylinositol levels, are difficult to reconcile with the current formulation of the inositol depletion hypothesis.

Objectives: A major hypothesis explaining the therapeutic effect of lithium (Li) in mania is depletion of inositol via inhibition of inositol monophosphatase. However, inositol is also present in the diet. Restriction of dietary inositol could theoretically enhance the effects of Li. Methods: We used dietary inositol restriction in animal studies and also devised a palatable diet for humans that is 90% free of inositol. Results: Dietary inositol restriction significantly augmented the inositol-reducing effect of Li in rat frontal cortex. Li reduced inositol levels by 4.7%, inositol-deficient diet by 5.1%, and Li plus inositol-deficient diet by 10.8%. However, feeding with the inositol-deficient diet did not enhance the behavioral effect of Li in the Li-pilocarpine seizure model. Fifteen patients participated in an open clinical study of the inositol-deficient diet: six rapid cycling bipolar patients responding inadequately to Li or valproate in different phases of illness; two Li-treated bipolar outpatients with residual symptomatology, and seven inpatient Li-treated bipolar patients in non-responding acute mania. The diet had a major effect in reducing the severity of affective disorder in 10 of the patients within the first 7–14 days of treatment. Conclusion: These results suggest that dietary inositol restriction may be useful in some bipolar patients, but controlled replication is necessary.

Jews have a low rate of alcohol use and abuse as reported in several different countries. In Israel over the last 10 years there has been a rising rate of alcoholism. We studied consecutive new admissions to our inpatient alcohol center, and an age and sex matched comparison group of patients consecutively admitted with schizophrenia for whether each of their four grandparents was Jewish, or non-Jewish. A significantly higher percentage of alcohol-related admissions were immigrants from the Former Soviet Union (FSU) than among schizophrenics. Among the alcohol-related admissions from the FSU, there were significantly fewer Jewish grandparents than among schizophrenia patients from the FSU. These data could support the concept that biological Jewish ethnicity has a protective effect against alcohol abuse, but are also consistent with cultural transmission of Jewish attitudes toward alcohol use.