Высокие дозы витамина D3 не влияют на риск возникновения депрессии

Background

Epidemiological evidence supports a relationship between vitamin D and mental well-being, although evidence from large-scale placebo-controlled intervention trials is lacking.

Aims

To examine if vitamin D supplementation has a beneficial effect on mood in community-dwelling older women; if a single annual large dose of vitamin D has a role in the prevention of depressive symptoms; and if there is an association between serum 25-hydroxyvitamin D levels and mental health.

Method

A double-blind, randomised, placebo-controlled trial of women aged 70 or older (the Vital D Study: ISRCTN83409867 and ACTR12605000658617). Participants were randomly assigned to receive 500 000 IU vitamin D3 (cholecalciferol) orally or placebo every autumn/winter for 3–5 consecutive years. The tools utilised at various time points were the General Health Questionnaire, the 12-item Short Form Health Survey, the Patient Global Impression–Improvement scale and the WHO Well-Being Index. Serum 25-hydroxyvitamin D levels were measured in a subset of 102 participants.

Results

In this non-clinical population, no significant differences between the vitamin D and placebo groups were detected in any of the measured outcomes of mental health. Serum 25-hydroxyvitamin D levels in the vitamin D group were 41% higher than the placebo group 12 months following their annual dose. Despite this difference, scores from the questionnaires did not differ. Furthermore, there was no interaction between those on antidepressant/anxiety medication at baseline and the treatment groups.

Conclusions

The lack of improvement in indices of mental well-being in the vitamin D group does not support the hypothesis that an annual high dose of vitamin D3 is a practical intervention to prevent depressive symptoms in older community-dwelling women.

Annual high-dose vitamin D3 and mental well-being: randomised controlled trial

Малые дозы лития могут предупреждать проблемы с памятью при болезни Альцгеймера

Low-dose lithium appears to slow the progression of memory loss and cognitive decline in individuals with amnestic mild cognitive impairment (aMCI), a significant risk factor for Alzheimer's disease (AD), a new study suggests.

A randomized, placebo-controlled trial showed treatment with lithium, an old drug historically used to treat bipolar disorder (BD) and major depression, was associated with a significant decrease in cerebrospinal fluid (CSF) concentrations of phosphorylated tau (P-tau) and better cognitive performance in individuals with aMCI. Furthermore, the drug was well tolerated and had a side effect profile similar to placebo.

Old Drug May Hold New Promise in Alzheimer's Disease

НПВС могут снижать эффективность СИОЗС

They then confirmed these effects in a human population. Depressed individuals who reported anti-inflammatory drug use were much less likely to have their symptoms relieved by an antidepressant than depressed patients who reported no anti-inflammatory drug use.

The effect was rather dramatic since, in the absence of any anti-inflammatory or analgesic use, 54 percent of patients responded to the antidepressant, wheh success rates dropped to approximately 40 percent for those who reported using anti-inflammatory agents.

Anti-Inflammatory Meds Can Reduce Antidepressant Effectiveness

Отсутствие эффективности диеты богатой омега-3 и омега-6 в предупреждении депрессии

Background: The associations between different sources of dietary n−3 (omega-3) and n−6 (omega-6) fatty acids and the risk of depression have not been prospectively studied.

Objective: The objective was to examine the relation between different n−3 and n−6 types with clinical depression incidence.

Design: We prospectively studied 54,632 US women from the Nurses' Health Study who were 50–77 y of age and free from depressive symptoms at baseline. Information on diet was obtained from validated food-frequency questionnaires. Clinical depression was defined as reporting both physician-diagnosed depression and regular antidepressant medication use.

Results: During 10 y of follow-up (1996–2006), 2823 incident cases of depression were documented. Intake of long-chain n−3 fatty acids from fish was not associated with depression risk [relative risk (RR) for 0.3 g/d increment: 0.99; 95% CI: 0.88, 1.10], whereas α-linolenic acid (ALA) intake was inversely associated with depression risk (multivariate RR for 0.5 g/d increment: 0.82; 95% CI: 0.71, 0.94]). The inverse association between ALA and depression was stronger in women with low linoleic acid (LA) intake (P for interaction = 0.02): a 0.5-g/d increment in ALA was inversely associated with depression in the first, second, and third LA quintiles [RR (95% CI): 0.57 (0.37, 0.87), 0.62 (0.41, 0.93), and 0.68 (0.47, 0.96), respectively] but not in the fourth and fifth quintiles.

Conclusions: The results of this large longitudinal study do not support a protective effect of long-chain n−3 from fish on depression risk. Although these data support the hypothesis that higher ALA and lower LA intakes reduce depression risk, this relation warrants further investigation.

Dietary intake of n−3 and n−6 fatty acids and the risk of clinical depression in women: a 10-y prospective follow-up study

Метаболические расстройства коморбидные с БАР

Chronic stress, which patients experience during both the manic and the depressive phases of bipolar disorder, is associated with increased cortisol levels, lack of cortisol suppression, and changes in hypothalamic-pituitary-adrenal axis responses. This metabolic dysregulation may increase insulin resistance and can lead to hyperglycemia, increased oxidative stress, metabolic syndrome, and atherosclerosis. In addition, patients with bipolar illness have increased activity of the sympathetic nervous system, which may also lead to insulin resistance, metabolic syndrome, and increased risk of sudden cardiac death.2

Depressive syndromes may be neurotoxic. Abnormalities in cellular plasticity, cellular resilience, and intracellular signaling, as well as alterations in the size, shape, and density of neurons and glia, have been found. Studies employing neuroimaging and neuropsychological tests have demonstrated abnormalities in brain morphology and function in patient populations with depressive syndromes and in those with diabetes. Common physiologic mechanisms have been implicated, including insulin-glucose homeostasis, immuno-inflammatory processes, and oxidative stress mechanisms.


Metabolic Comorbidities in Patients With Bipolar Disorder

Новые возможности для лечения биполярной депрессии

Riluzole, an inhibitor of glutamate release, is approved by the FDA for the treatment of amyotrophic lateral sclerosis. This agent, at a dosage of 50 to 200 mg/d, was evaluated in an 8-week add-on study in combination with lithium in 14 adults with bipolar depression, 6 of whom had bipolar I disorder, and 8 of whom had bipolar II disorder. Eight patients completed the 8-week trial.6 Significant improvement in depressive symptoms was noted in weeks 5 through 8 as measured by the Montgomery Asberg Depression Rating Scale (MADRS).

Ketamine is a noncompetitive NMDA antagonist that has been evaluated in subanesthetic doses in persons with bipolar disorder.7 Results from a double-blind, randomized, placebo-controlled, crossover study indicate that a single intravenous infusion of ketamine combined with lithium or valproate was capable of alleviating depressive symptoms within 40 minutes of administration when compared with placebo.7 The benefit of ketamine was sustained through day 3. Overall, 71% of patients responded to ketamine and 6% responded to placebo at some point during the trial. Ketamine was not associated with significant increases in hypomania or mania but was associated with dissociative symptoms.

Several case reports and case series suggest that insulin sensitizers (eg, rosiglitazone) may offer an antidepressant effect in persons with major depressive disorder. Studies are currently under way in bipolar disorder. For example, several studies are evaluating the antidepressant effects of intranasal insulin and insulin secretagogues (eg, incretins) in bipolar disorder. Moreover, there is ongoing research to determine whether weight loss, bariatric surgery, and dietary modification (eg, ketogenic diet) improve depressive symptoms in persons with bipolar disorder.

Novel Treatment Avenues for Bipolar Depression

Блокирование 5-HT7 рецепторов как потенциальный механизм быстрого антидепрессивного эффекта

Current antidepressants still display unsatisfactory efficacy and a delayed onset of therapeutic action. Here we show that the pharmacological blockade of serotonin 7 (5-HT7) receptors produced a faster antidepressant-like response than the commonly prescribed antidepressant fluoxetine. In the rat, the selective 5-HT7 receptor antagonist SB-269970 counteracted the anxiogenic-like effect of fluoxetine in the open field and exerted an antidepressant-like effect in the forced swim test. In vivo, 5-HT7 receptors negatively regulate the firing activity of dorsal raphe 5-HT neurons and become desensitized after long-term administration of fluoxetine. In contrast with fluoxetine, a 1-week treatment with SB-269970 did not alter 5-HT firing activity but desensitized cell body 5-HT autoreceptors, enhanced the hippocampal cell proliferation, and counteracted the depressive-like behavior in olfactory bulbectomized rats. Finally, unlike fluoxetine, early-life administration of SB-269970, did not induce anxious/depressive-like behaviors in adulthood. Together, these findings indicate that the 5-HT7 receptor antagonists may represent a new class of antidepressants with faster therapeutic action.

Pharmacological Blockade of 5-HT7 Receptors as a Putative Fast Acting Antidepressant Strategy

Дексаметазоновый тест и критерии DSM

Starting from discoveries in the early 19th century about the basics of the endocrine system, it traces the identification of adrenal steroids in the early 20th century and finally the landmark clinical studies of the 1970s and 1980s that almost resulted in the DST becoming a standard of psychiatric diagnosis. Unfortunately, DSM-III diagnostic criteria did not reliably identify patients with positive DST results. Instead of questioning the DSM criteria, the DST was discarded as faulty.

Endocrine Psychiatry: The Dexamethasone Suppression Test and Electroconvulsive Therapy

Глутаматергические лекарственные средства для лечения шизофрении

Glutamatergic drugs in development

Target	Proposed mechanism	Proposed agents	Phase of development
Glycine/D-serine receptor	Allosteric modulator of the NMDA receptor	Glycine, D-serine, D-alanine, D-cycloserine	Phase II
Glycine-type I transport inhibitor	Blocks the reuptake of glycine, akin to SSRIs’ action on serotonin	Sarcosine, RG1678	Phase II/III
Metabotropic glutamate type 2/3 (mGluR2/3)	Blocks presynaptic glutamate release	LY-2140023	Phase II
Redox sensitive site	Allosteric modulator of the NMDA receptor	N-acetylcysteine	Phase II
D-amino acid oxidase (DAAO) inhibitors	Inhibits the enzyme that metabolizes D-serine	Remains in preclinical stage
Tetrahydrobiopterin (BH4)	Indirectly modulates glutamatergic system	Remains in preclinical stage
NMDA: N-methyl-D-aspartate; SSRIs: selective serotonin reuptake inhibitors

Glycine/D-serine site agonists. To date, most studies have used glutamatergic drugs adjunctive to antipsychotics and targeted the glycine/D-serine modulatory site, in part because glycine and D-serine are natural compounds and therefore FDA approval for their use could be obtained without the extensive preclinical development usually required for new chemical entities.¹⁶ Unfortunately, these agents are less potent than traditional pharmaceuticals, and delivering optimal doses may be impossible. Nevertheless, positive studies with these compounds have provided proof-of-concept for development of agents with higher affinity and specificity.

Studies have used glycine administered at doses up to 60 g/d, D-serine up to 8 g/d, or D-alanine approximately 6 g/d. For glycine, 60 g/d is the highest dose that can be given because of concerns about tolerability and replacement of other essential amino acids. D-serine originally was tested at approximately 2 g/d with promising results, but a recent open-label trial suggested that higher doses may be more efficacious.¹⁷ D-serine doses are limited by potential renal toxicity, as demonstrated in rodents studies.

Although not all studies of glycine/D-serine site agonists have been positive, a recent meta-analysis suggests significant improvement in negative symptoms across studies.¹⁸ Variability in statistical results across studies is related primarily to degree of placebo effect within individual trials, with a mean improvement in negative symptoms of approximately 15%. Glycine/D-serine site agonists seem to be less effective when combined with clozapine, possibly because clozapine may already enhance the glutamatergic system and increase synaptic glycine levels.⁶

One study that evaluated effects of open-label glycine in individuals with schizophrenia symptoms observed a large effect-size improvement, including early remission in 3 of 10 patients.¹⁹ These data—if confirmed by double-blind trials—would indicate that glycine/d-serine site agonists might have utility in treating the schizophrenia prodrome.

Glycine transport inhibitors. A potential indirect approach to raising glycine levels in the brain is using GlyT1-type glycine transport inhibitors (GTIs). GlyT1 transporters are co-localized in brain with NMDARs and modulate local glycine levels. Rather than binding directly to the NMDAR glycine binding site, GTIs increase glycine levels in the synapse by preventing its removal by GlyT1 transporters. Their function is analogous to using selective serotonin reuptake inhibitors to increase serotonin levels in patients with depression.⁶

Sarcosine (N-methylglycine) is a naturally occurring GlyT1 inhibitor that has been used in early clinical trials in Taiwan. Initial studies with sarcosine showed efficacy similar to—and in some cases better than—that of direct glycine/D-serine site agonists when added to first-generation or non-clozapine second-generation antipsychotics.¹⁸ Sarcosine also has been found to be effective for acute treatment of schizophrenia.²⁰ At present, however, sarcosine is not available for experimental use in the United States because of toxicity considerations.

Using high-affinity GTIs for schizophrenia was first proposed in the mid-1990s,⁶ but such compounds are only now entering clinical efficacy studies. Most recently, phase II results were presented for RG1678, a compound developed by Hoffman LaRoche.²¹ The study targeted persistent negative symptoms in patients receiving chronic antipsychotic treatment. Adding RG1678, 10 mg and 30 mg, to antipsychotics led to significant improvement in persistent negative symptoms vs placebo. These promising results are being followed up in phase III studies.

Other glutamatergic options. Few compounds are available to modulate NMDARs at sites other than the glycine/D-serine site. One study administered N-acetylcysteine, a glutathione precursor, as a potential treatment for persistent negative symptoms.²² Encouraging clinical results were observed in this double-blind study, along with improvement in electrophysiologic measures, negative symptoms, and overall functioning, but the study was limited by relatively high rates of noncompletion. Preclinical studies have combined D-serine with an inhibitor of D-amino acid oxidase to prevent D-serine breakdown.²³ In rodents, this approach produces a 30-fold increase in D-serine potency.

Tetrahydrobiopterin (BH₄) is a cofactor for enzymes responsible for the synthesis of dopamine and other monoamines, and presynaptic release of dopamine and glutamate. Reductions in BH₄ levels have been reported in schizophrenia, which suggests that this compound may be etiologically important.²⁴ Researchers have initiated a study of this compound in schizophrenia.

Other schizophrenia models propose that the crucial issue is not NMDA blockade but subsequent dysregulation of presynaptic glutamate release. Type 2/3 metabotropic glutamate receptors (mGluR2/3) are located on presynaptic glutamate terminals and inhibit presynaptic glutamate release. mGluR2/3 agonists have been shown to reverse ketamine’s effects in humans and in animal models,^25,26 which suggests a potential role in schizophrenia treatment.

The first mGluR2/3 agonist entered into monotherapy clinical efficacy trials for schizophrenia was LY-2140023. In an initial trial, this compound showed significant efficacy in improving positive and negative symptoms, comparable to that of olanzapine.²⁷ However, a follow-up study failed because of a large placebo effect,²⁸ which leaves the efficacy question unresolved.In contrast to mGluR2/3, type 5 metabotropic receptors (mGluR5) are co-localized with NMDA receptors and potentiate activation. Thus, mGluR5 agonists also may be effective for treating schizophrenia. These compounds remain in preclinical development. Other approaches, such as stimulating specific types of GABA receptors to overcome glutamatergic deficits, remain promising but have not been tested in definitive clinical trials.
Glutamate: New hope for schizophrenia treatment

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