Normobaric oxygen treatment for mild-to-moderate depression: a randomized, double-blind, proof-of-concept trial.

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).

A multi-national, multi-disciplinary Delphi consensus study on using omega-3 polyunsaturated fatty acids (n-3 PUFAs) for the treatment of major depressive disorder.

INTRODUCTION: Omega-3 polyunsaturated fatty acids (n-3 PUFAs) are recommended as an integrative treatment for major depressive disorder (MDD). In 2019, the International Society for Nutritional Psychiatry Research (ISNPR) developed the first practice guidelines for n-3 PUFA treatment of MDD. To strengthen these guidelines and enhance their clinical applicability, we synthesized the evidence and clinical experiences previously obtained through the Delphi methodology. METHODS: Nineteen statements covering five major domains in MDD treatment were formulated through internal meetings. Fourteen international experts were invited to participate in the web-based Delphi process that validated the statements. Likert scales were used, and consensus level was set at 7.0/10.0, with the equivocal level set at 5.1-6.9. The items with scores < 5.0 were allocated into a second round Delphi survey with inverse questions. RESULTS: All panelists completed the survey. Sixteen statements reached consensus, and the statement "n-3 PUFAs are one of the potential adjunctive treatments for adult MDD" reached the highest agreement. "N-3 PUFAs are one of the potential monotherapies for adult MDD" instead scored lowest. Regarding "special populations," many items, reached high consensus despite sub-optimal supportive evidence. LIMITATION: The panelists had a specialized interest in n-3 PUFAs; focus was placed on clinical issues rather than on biological mechanisms. CONCLUSIONS: The Delphi process helps bridge the gap between scientific evidence and clinical practice, supports certain uses of PUFA and identifies insufficiency in current evidence that merit future research.

International Society for Nutritional Psychiatry Research Practice Guidelines for Omega-3 Fatty Acids in the Treatment of Major Depressive Disorder.

Major depressive disorder (MDD) is a complex mental illness with unmet therapeutic needs. The antidepressant effects of ω-3 polyunsaturated fatty acids (n-3 PUFAs) have been widely reported. The subcommittee of the International Society for Nutritional Psychiatry Research organized an expert panel and conducted a literature review and a Delphi process to develop a consensus-based practice guideline for clinical use of n-3 PUFAs in MDD. The guideline focuses on 5 thematic areas: general concepts, acute treatment strategy, depression recurrence monitoring and prevention, use in special populations, and potential safety issues. The key practice guidelines contend that: (1) clinicians and other practitioners are advised to conduct a clinical interview to validate clinical diagnoses, physical conditions, and measurement-based psychopathological assessments in the therapeutic settings when recommending n-3 PUFAs in depression treatment; (2) with respect to formulation and dosage, both pure eicosapentaenoic acid (EPA) or an EPA/docosahexaenoic acid (DHA) combination of a ratio higher than 2 (EPA/DHA >2) are considered effective, and the recommended dosages should be 1-2 g of net EPA daily, from either pure EPA or an EPA/DHA (>2:1) formula; (3) the quality of n-3 PUFAs may affect therapeutic activity; and (4) potential adverse effects, such as gastrointestinal and dermatological conditions, should be monitored, as well as obtaining comprehensive metabolic panels. The expert consensus panel has agreed on using n-3 PUFAs in MDD treatment for pregnant women, children, and the elderly, and prevention in high-risk populations. Personalizing the clinical application of n-3 PUFAs in subgroups of MDD with a low Omega-3 Index or high levels of inflammatory markers might be regarded as areas that deserve future research.

Solar insolation in springtime influences age of onset of bipolar I disorder.

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.

Second language as a compensatory resource for maintaining verbal fluency in bilingual immigrants with schizophrenia.

BACKGROUND AND OBJECTIVES: Due to the large migrations over the past three decades, large numbers of individuals with schizophrenia are learning a second language and being seen in clinics in that second language. We conducted within-subject comparisons to clarify the contribution of clinical, linguistic and bilingual features in the first and second languages of bilinguals with schizophrenia. METHODS: Ten bilingual Russian(L1) and Hebrew(L2) proficient patients, who developed clinical schizophrenia after achieving proficiency in both languages, were selected from 60 candidates referred for the study; they were resident in Israel 7-32 years with 3-10 years from immigration to diagnosis. Clinical, linguistic and fluency markers were coded in transcripts of clinical interviews. RESULTS: There was a trend toward more verbal productivity in the first language (L1) than the second language (L2). Clinical speech markers associated with thought disorder and cognitive impairment (blocking and topic shift) were similar in both languages. Among linguistic markers of schizophrenia, Incomplete syntax and Speech role reference were significantly more frequent in L2 than L1; Lexical repetition and Unclear reference demonstrated a trend in the same direction. For fluency phenomena, Discourse markers were more prevalent in L1 than L2, and Codeswitching was similar across languages, showing that the patients were attuned to the socio-pragmatics of language use. CONCLUSIONS: More frequent linguistic markers of schizophrenia in L2 show more impairment in the syntactic/semantic components of language, reflecting greater thought and cognitive dysfunction. Patients are well able to acquire a second language. Nevertheless, schizophrenia finds expression in that language. Finally, more frequent fluency markers in L1 suggests motivation to maintain fluency, evidenced in particular by codeswitched L2 lexical items, a compensatory resource.

Lithium nephrotoxicity.

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.

Molecular effects of lithium are partially mimicked by inositol-monophosphatase (IMPA)1 knockout mice in a brain region-dependent manner.

We have previously shown that homozygote knockout (KO) of inositol-monophosphatase1 (IMPA1) results in lithium (Li)-like behavior. We now aimed to find out whether Li-treated mice and IMPA1 KO mice exhibit neurochemical similarity at the gene- and protein-expression level. Hippocampal and frontal cortex B-cell lymphoma (Bcl-2), Bcl-2-associated X protein (BAX), P53, Perodoxin2 (PRDX2), myristoylated alanine-rich C kinase substrate (MARCKS) and neuropeptide Y (NPY) mRNA levels, and hippocampal, frontal cortex and hypothalamic cytokine levels, all previously reported to be affected by lithium treatment, were measured in three groups of mice: wildtype (WT) on regular-food (RF), WT on Li-supplemented food (Li-treated) and IMPA1-KOs. Hippocampal and frontal cortex Bcl-2 and MARCKS were the only genes commonly affected (downregulated) by Li and IMPA1 KO; Bcl-2 - by 28% and 19%, respectively; MARCKS - by about 20% in both regions. The effect of Li and of IMPA1 KO on cytokine levels differed among the three brain areas studied. Only in the hippocampus both interventions exerted similar effects. Frontal cortex cytokine levels were unaffected neither by Li nor by IMPA1 KO. Similar changes in Bcl-2 and MARCKS but not in PRDX2 and NPY following both Li-treatment and IMPA1 KO suggest a mechanism different than inositol-monophosphatase1 inhibition for Li׳s effect on the latter genes. The cytokine levels results suggest that the mechanism mediating Li׳s effect on the inflammatory system differs among brain regions. Only in the hippocampus the results favor the involvement of the phosphatidylinositol (PI) cycle.

Chronic Lithium Treatment Enhances the Number of Quiescent Neural Progenitors but Not the Number of DCX-Positive Immature Neurons.

BACKGROUND: The term adult neurogenesis constitutes a series of developmental steps including the birth, survival, differentiation, maturation, and even death of newborn progenitor cells within neurogenic niches. Within the hippocampus progenitors reside in the neurogenic niche of the subgranular zone in the dentate gyrus subfield. At the different stages, designated type-I, type-IIa, type-IIb, type-III, and granule cell neurons, the cells express a series of markers enabling their identification and visualization. Lithium has been shown to increase hippocampal cell proliferation in the subgranular zone of the hippocampal dentate gyrus subfield of adult rodents and to stimulate the proliferation of hippocampal progenitor cells in vitro, but data regarding lithium's ability to increase neuronal differentiation and survival is equivocal. METHODS: To clarify the effect of lithium on adult hippocampal neurogenesis, we identified the effect of chronic lithium treatment on distinct stages of hippocampal progenitor development using adult Nestin-green fluorescent protein transgenic mice and immunofluorescent techniques. RESULTS: The present observations confirm that lithium targets the initial stages of progenitor development enhancing the turnover of quiescent neural progenitors/putative stem-cells, corroborating previous reports. However, the enhanced quiescent neural progenitor-turnover does not translate into an increased number of immature neurons. We also observed a steep decline in the number of type-III immature neurons with complex tertiary-dendrites, suggesting that lithium alters the morphological maturation of newborn neurons. CONCLUSIONS: Our results do not corroborate previous reports of lithium-induced enhanced numbers of newly generated neurons.

Inositol-deficient food augments a behavioral effect of long-term lithium treatment mediated by inositol monophosphatase inhibition: an animal model with relevance for bipolar disorder.

Lithium treatment in rodents markedly enhances cholinergic agonists such as pilocarpine. This effect can be reversed in a stereospecific manner by administration of inositol, suggesting that the effect of lithium is caused by inositol monophosphatase inhibition and consequent inositol depletion. If so, inositol-deficient food would be expected to enhance lithium effects. Inositol-deficient food was prepared from inositol-free ingredients. Mice with a homozygote knockout of the inositol monophosphatase 1 gene unable to synthesize inositol endogenously and mimicking lithium-treated animals were fed this diet or a control diet. Lithium-treated wild-type animals were also treated with the inositol-deficient diet or control diet. Pilocarpine was administered after 1 week of treatment, and behavior including seizures was assessed using rating scale. Inositol-deficient food-treated animals, both lithium treated and with inositol monophosphatase 1 knockout, had significantly elevated cholinergic behavior rating and significantly increased or earlier seizures compared with the controls. The effect of inositol-deficient food supports the role of inositol depletion in the effects of lithium on pilocarpine-induced behavior. However, the relevance of this behavior to other more mood-related effects of lithium is not clear.

Influence of birth cohort on age of onset cluster analysis in bipolar I disorder.

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.

Inositol-related gene knockouts mimic lithium's effect on mitochondrial function.

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.

Acute intracerebroventricular inositol does not reverse the effect of chronic lithium treatment in the forced swim test.

BACKGROUND: Lithium has numerous biochemical effects but it is difficult to dissect which of these is responsible for its therapeutic action in bipolar disorder. In the current study we aimed to address one of the major hypotheses, the inositol depletion hypothesis. This hypothesis postulates that lithium's mood-stabilizing effect is mediated by the depletion of brain inositol levels and the subsequent effect on cellular signaling. METHODS: We studied whether acute intracerebroventricular (ICV) administration of myo-inositol could reverse the antidepressant-like effect of chronic lithium treatment in the forced swim test (FST). RESULTS: In contrast with our prediction, acute myo-inositol administration did not reverse the effect of chronic lithium to decrease immobility in the FST. CONCLUSIONS: The results of the present study are limited due to the following: (1) inositol was given acutely while possible events downstream of inositol depletion might require a longer period and (2) ICV inositol may not have reached those areas of the brain involved in the FST.

Trehalose induced antidepressant-like effects and autophagy enhancement in mice.

RATIONALE: The disaccharide trehalose protects cells from hypoxic and anoxic injury and suppresses protein aggregation. In vivo studies with trehalose show cellular and behavioral beneficial effects in animal models of neurodegenerative diseases. Moreover, trehalose was shown to enhance autophagy, a process that had been recently suggested to be involved in the therapeutic action of antidepressant and mood-stabilizing drugs. OBJECTIVE: The present study was therefore designed to explore antidepressant and mood-stabilizing activity of trehalose in animal models for depression and mania. METHODS: Trehalose 1 or 2% was administered for 3 weeks as a drinking solution to Black Swiss mice (a model of manic-like behaviors) or 2% to ICR mice and their behavior evaluated in a number of tests related to depression or mania. The effects of trehalose were compared with similar chronic administration of the disaccharide maltose as well as with a vehicle (water) control. RESULTS: Chronic administration of trehalose resulted in a reduction of frontal cortex p62/beclin-1 ratio suggesting enhancement of autophagy. Trehalose had no mood-stabilizing effects on manic-like behavior in Black Swiss mice but instead augmented amphetamine-induced hyperactivity, an effect similar to antidepressant drugs. In ICR mice, trehalose did not alter spontaneous activity or amphetamine-induced hyperactivity but in two separate experiments had a significant effect to reduce immobility in the forced swim test, a standard screening test for antidepressant-like effects. CONCLUSIONS: The results suggest that trehalose may have antidepressant-like properties. It is hypothesized that these behavioral changes could be related to trehalose effects to enhance autophagy.

Inhibition of inositol monophosphatase (IMPase) at the calbindin-D28k binding site: molecular and behavioral aspects.

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 monophosphatase inhibitor L-690,330 affects pilocarpine-behavior and the forced swim test.

RATIONALE: 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. OBJECTIVES: 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). METHODS: The inhibitor was administered intracerebroventricularly in liposomes. RESULTS: L-690,330 increased the sensitivity to subconvulsive doses of pilocarpine and decreased immobility time in the FST. CONCLUSIONS: 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.