Clinical and pharmacological factors influencing serum clozapine and norclozapine levels.

Background: Clozapine (CLO) is a very effective antipsychotic, whose use is associated with dose-dependent risk of complications. Due to high interindividual variability in CLO metabolism, there is a need to identify factors affecting the blood concentrations of CLO and its active metabolite, norclozapine (NCLO). Methods: A total of 446 blood samples (collected from 233 women and 213 men, aged from 18 to 77 years) were included in this study and analyzed for CLO and NCLO concentrations. The patients were treated at a psychiatric hospital in Warsaw in the years 2016-2021. Serum CLO and NCLO concentrations were determined with high-performance liquid chromatography coupled to UV. Results: The following factors were shown to increase serum CLO and NCLO levels: higher CLO dose (p < 0.001), female sex (p < 0.001), nonsmoker status (p < 0.001), the use of more than two additional psychotropic drugs (only in the case of CLO; p = 0.046), concomitant use of beta-blockers (for CLO p = 0.049; for NCLO p < 0.001), and older age (for CLO p < 0.001; for NCLO p = 0.011). Despite the use of CLO at daily doses within the recommended range (200-450 mg), the evaluated serum CLO and NCLO levels were within the therapeutic ranges in only 37% and 75% of cases, respectively, with 5.6% of cases exceeding the CLO toxicity threshold. Discussion: The use of CLO at recommended doses does not guarantee achieving therapeutic concentrations of CLO or NCLO. Women and nonsmokers were at the highest risk of having toxic CLO levels.

Placebo-controlled randomized clinical trials of antidepressants for major depressive disorder: Analysis of ClinicalTrials.gov, 2008-2022.

The purpose of this study was to analyze the key aspects of the design of contemporary placebo-controlled randomized clinical trials (RCTs) of antidepressants enrolling patients with major depressive disorder (MDD) aged 18 years or older, especially the outcome measures and the eligibility criteria. The study included 122 RCTs registered with ClinicalTrials.gov and started from 2008 through 2022. Most RCTs assessed only clinical remission, with proportion of trials with outcome measures related to functional remission being rather low (n = 34; 28 %). Clinical remission was mostly evaluated in acute phase of depression, and only 7 (6 %) trials assessed the prevention of relapse. Proportion of trials utilizing self-report questionnaires that provide important information complementary to clinician-rated scales was moderate (n = 66; 54 %). Another problem in included RCTs was common use of stringent eligibility criteria. For instance, minimal symtpom severity required for the patient's inclusion was listed in 104 RCTs (85 %), and 41 RCTs (34 %) excluded patients based on comorbid anxiety disorders. Most RCTs (n = 103; 84 %) excluded older patients, and only 6 (5 %) trials were dedicated exclusively to them. To ensure optimal development of clinical pharmacotherapy of MDD, the investigators should consider modification of some of the key aspects of the design of RCTs of antidepressants.

Depression, anxiety, insomnia and interleukins in the early postpartum period.

Background: Some new mothers have been shown to suffer from anxiety and depression associated with insomnia during the postpartum period. Our study assessed the impact of demographic, psychopathological, and biochemical factors on the incidence of depression in women during the early postpartum period. Methods: A total of 119 women were evaluated at 24-48 h postpartum with the following psychometric scales: Hamilton Depression Rating Scale (HDRS), Edinburgh Postnatal Depression Scale (EPDS), Hamilton Anxiety Rating Scale (HARS) and Athens Insomnia Scale (AIS). In addition, blood was drawn to assay interleukin 6 (IL-6) and interleukin 10 (IL-10). Results: The factors that had the greatest impact on the risk of postpartum depression detected with the HDRS were high HARS scores and evidence of insomnia in the AIS. There were no significant differences in IL-6 or IL-10 levels in women with and without depression (based on either HDRS or EPDS scores) and insomnia (based on AIS) after childbirth. Considering demographic factors, divorced and single women were shown to be at higher risk of postpartum depression (based on EPDS scores). Limitations: Small sample size and short observation span. Conclusion: This study highlights the relationship between postpartum depression and both anxiety and insomnia and emphasises the importance to assess symptoms of anxiety and sleep quality as part of screening in women at risk of postpartum depression.

Factors Contributing to Risk of Persistence of Positive and Negative Symptoms in Schizophrenia during Hospitalization.

The aim of the study was to evaluate factors that may contribute to the persistence of positive, negative and other psychopathological symptoms of schizophrenia. All patients were treated in general psychiatric wards between January 2006 and December 2017. The initial study sample comprised of the medical reports of 600 patients. The main, specified inclusion criterion for the study was schizophrenia as a discharge diagnosis. Medical reports of 262 patients were excluded from the study due to no neuroimaging scans being available. The symptoms were categorised into three groups: positive, negative, and other psychopathological symptoms. The statistical analysis comprised modalities such as demographic data, clinical symptoms, as well as neuroimaging scans linking them to a potential impact of sustaining the mentioned groups of symptoms during the period of hospitalization. The analysis revealed that statistically significant risk factors of persistence of the three groups of symptoms are the elderly age, the increasing toll of hospitalizations, suicidal attempts in medical history, a family history of alcohol abuse, the presence of positive, negative and other psychopathological symptoms on admission to the hospital, as well as the absence of cavum septi pellucidi (CSP). The study showed that addiction to psychotropic drugs and a family history of schizophrenia were more frequent in patients with persistent CSP.

The role of the L-arginine-NO-cGMP-dependent pathway in the development of sensitization to mephedrone effects on the locomotor activity in mice.

Mephedrone, a popular psychostimulating substance widely used illegally in recreational purposes, exerts in rodents that regularly and intermittently were exposed to it a sensitized response to the drug. Behavioral sensitization is one of experimental models of drug dependency/abuse liability. In the present study we evaluated a potential involvement of the L-arginine-NO-cGMP pathway in the development of sensitization to the mephedrone-induced hyperlocomotion. Locomotor activity was measured automatically and experiments were performed on male Albino Swiss mice. We demonstrated that a 5-day administration of 7-nitroindazole (10 or 20 mg/kg/day) and L-NAME (50 mg/kg/day) suppressed the development of sensitization to the mephedrone-induced hyperlocomotion. As for L-arginine (125 or 250 mg/kg/day) and methylene blue (5 or 10 mg/kg/day) the obtained outcomes are inconclusive. Furthermore, the lower dose of L-NAME (25 mg/kg/day) surprisingly potentiated the development of sensitization to the mephedrone-induced effects on the spontaneous locomotor activity in mice. In conclusion, our data demonstrated that modulators of the L-arginine-NO-cGMP pathway may differently affect the development of sensitization to the locomotor stimulant effects of mephedrone. Inhibition of neuronal nitric oxide synthase (NOS) seems to prevent this process quite profoundly, non-selective inhibition of NOS may have a dual effect, whereas inhibition of soluble guanylate cyclase may only partially suppress the development of sensitization to the mephedrone-induced effects.

Central Effects of the Designer Drug Mephedrone in Mice-Basic Studies.

Mephedrone belongs to the "party drugs" thanks to its psychostimulant effects, similar to the ones observed after amphetamines. Though mephedrone is used worldwide by humans and in laboratory animals, not all properties of this drug have been discovered yet. Therefore, the main aim of this study was to expand the knowledge about mephedrone's activity in living organisms. A set of behavioral tests (i.e., measurement of the spontaneous locomotor activity, rotarod, chimney, elevated plus maze with its modification, novel object recognition, and pentylenetetrazol seizure tests) were carried out in male albino Swiss mice. Different dose ranges of mephedrone (0.05-5 mg/kg) were administered. We demonstrated that mephedrone at a dose of 5 mg/kg rapidly increased the spontaneous locomotor activity of the tested mice and its repeated administration led to the development of tolerance to these effects. Mephedrone showed the anxiolytic-like potential and improved spatial memory, but it did not affect recognition memory. Moreover, the drug seemed not to have any anticonvulsant or proconvulsant activity. In conclusion, mephedrone induces many central effects. It easily crosses the blood-brain barrier and peaks in the brain quickly after exposure. Our experiment on inducing a hyperlocomotion effect showed that mephedrone's effects are transient and lasted for a relatively short time.

The Microbiota-Gut-Brain Axis as a Key to Neuropsychiatric Disorders: A Mini Review.

The central nervous system (CNS) is closely related to the gastrointestinal tract, mainly through regulating its function and homeostasis. Simultaneously, the gut flora affects the CNS and plays an essential role in the pathogenesis of neurologic and neuropsychological disorders such as Parkinson's and Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis or autism spectrum disorder. The population of gut microorganisms contains more than one billion bacteria. The most common are six phyla: Proteobacteria, Actinomyces, Verucomicrobia, Fusobacteria, and dominant Bacteroides with Firmicutes. The microbiota-gut-brain axis is a bidirectional nervous, endocrine, and immune communication between these two organs. They are connected through a variety of pathways, including the vagus nerve, the immune system, microbial metabolites such as short-chain fatty acids (SCFAs), the enteric nervous system, and hormones. Age, diet, antibiotics influence the balance of gut microorganisms and probably lead to the development of neurodegenerative disorders. In this article, a review is presented and discussed, with a specific focus on the changes of gut microbiota, gut-brain axis, related disorders, and the factors that influence gut imbalance.

Migraine and Its Association with Hyperactivity of Cell Membranes in the Course of Latent Magnesium Deficiency-Preliminary Study of the Importance of the Latent Tetany Presence in the Migraine Pathogenesis.

So far, there is no consistent and convincing theory explaining the pathogenesis of migraines. Vascular disorders, the effect of oxidative stress on neurons, and the contribution of magnesium-calcium deficiencies in triggering cortical depression and abnormal glutaminergic neurotransmission are taken into account. However, there are no reliable publications confirming the role of dietary deficits of magnesium and latent tetany as factors triggering migraine attacks. The aim of the study was to evaluate the influence of latent magnesium deficiency assessed with the electrophysiological tetany test on the course of migraine. The study included: a group of 35 patients (29 women and six men; in mean age 41 years) with migraine and a control group of 24 (17 women and seven men; in mean age 39 years) healthy volunteers. Migraine diagnosis was based on the International Headache Society criteria, 3rd edition. All patients and controls after full general and neurological examination were subjected to a standard electrophysiological ischemic tetany test. Moreover, the level of magnesium in blood serum was tested and was in the normal range in all patients. Then, the incidence of a positive tetany EMG test results in the migraine group and the results in the subgroups with and without aura were compared to the results in the control group. Moreover, the relationship between clinical markers of spasmophilia and the results of the tetany test was investigated in the migraine group. As well as the relationship between migraine frequency and tetany test results. There was no statistically significant difference in the occurrence of the electrophysiological exponent of spasmophilia between the migraine and control group. Neither correlation between the occurrence of clinical symptoms nor the frequency of migraine attacks and the results of the tetany test was stated (p > 0.05). However, there was an apparent statistical difference between the subgroup of migraine patients with aura in relation to the control group (p < 0.05). The result raises hope to find a trigger for migraine attacks of this clinical form, the more that this factor may turn out to be easy to supplement with dietary supplementation.

Pharmaco-Electroencephalography-Based Assessment of Antidepressant Drug Efficacy-The Use of Magnesium Ions in the Treatment of Depression.

Pharmaco-electroencephalography (pharmaco-EEG) is a technique used to assess the effects of psychotropic medications on the bioelectrical activity of the brain. The purpose of this study was to assess the treatment response with the use of the Hamilton Depression Rating Scale (HDRS) and via EEG. Over an 8-week period, we analyzed electroencephalographic tracings of 91 patients hospitalized for major depression at the Medical University of Warsaw. Thirty-nine of those patients received tricyclic antidepressants (TCAs), 35 received fluoxetine, and 17 received fluoxetine augmented with magnesium (Mg) ions. All patients had their serum drug levels monitored. The highest proportion of patients (88.2%) who showed adequate responses to treatment was observed in the fluoxetine+Mg group, whereas the lowest rates of treatment response were observed in the TCA group (58.3%). This difference was statistically significant (p = 0.029, Phi = 0.30). Our study demonstrated a relationship between achieving remission (HDRS ≤ 6 at week 8 of treatment) and obtaining a positive pharmaco-EEG profile 6 h after administration of the first dose in the group receiving fluoxetine augmented with Mg ions (p = 0.035, Phi = 0.63).

The Interaction of Selective A1 and A2A Adenosine Receptor Antagonists with Magnesium and Zinc Ions in Mice: Behavioural, Biochemical and Molecular Studies.

The purpose of the study was to investigate whether the co-administration of Mg2+ and Zn2+ with selective A1 and A2A receptor antagonists might be an interesting antidepressant strategy. Forced swim, tail suspension, and spontaneous locomotor motility tests in mice were performed. Further, biochemical and molecular studies were conducted. The obtained results indicate the interaction of DPCPX and istradefylline with Mg2+ and Zn2+ manifested in an antidepressant-like effect. The reduction of the BDNF serum level after co-administration of DPCPX and istradefylline with Mg2+ and Zn2+ was noted. Additionally, Mg2+ or Zn2+, both alone and in combination with DPCPX or istradefylline, causes changes in Adora1 expression, DPCPX or istradefylline co-administered with Zn2+ increases Slc6a15 expression as compared to a single-drug treatment, co-administration of tested agents does not have a more favourable effect on Comt expression. Moreover, the changes obtained in Ogg1, MsrA, Nrf2 expression show that DPCPX-Mg2+, DPCPX-Zn2+, istradefylline-Mg2+ and istradefylline-Zn2+ co-treatment may have greater antioxidant capacity benefits than administration of DPCPX and istradefylline alone. It seems plausible that a combination of selective A1 as well as an A2A receptor antagonist and magnesium or zinc may be a new antidepressant therapeutic strategy.

Effects of Magnesium Supplementation on Unipolar Depression: A Placebo-Controlled Study and Review of the Importance of Dosing and Magnesium Status in the Therapeutic Response.

Animal studies using tests and models have demonstrated that magnesium exerts an antidepressant effect. The literature contains few studies in humans involving attempts to augment antidepressant therapy with magnesium ions. The purpose of our study was to assess the efficacy and safety of antidepressant treatment, in combination with magnesium ions. A total of 37 participants with recurrent depressive disorder who developed a depressive episode were included in this study. As part of this double-blind study, treatment with the antidepressant fluoxetine was accompanied with either magnesium ions (120 mg/day as magnesium aspartate) or placebo. During an 8-week treatment period, each patient was monitored for any clinical abnormalities. Moreover, serum fluoxetine and magnesium levels were measured, and pharmaco-electroencephalography was performed. The fluoxetine + magnesium and fluoxetine + placebo groups showed no significant differences in either Hamilton Depression Rating Scale (HDRS) scores or serum magnesium levels at any stage of treatment. Multivariate statistical analysis of the whole investigated group showed that the following parameters increased the odds of effective treatment: lower baseline HDRS scores, female gender, smoking, and treatment augmentation with magnesium. The parameters that increased the odds of remission were lower baseline HDRS scores, shorter history of disease, the presence of antidepressant-induced changes in the pharmaco-EEG profile at 6 h after treatment, and the fact of receiving treatment augmented with magnesium ions. The limitation of this study is a small sample size.

Insomnia, postpartum depression and estradiol in women after delivery.

After childbirth, women may develop symptoms of depression with the associated sleep disturbances. This study assessed the relationship between insomnia and both depression symptoms and blood estradiol levels in women during the early postpartum period. 84 patients were assessed 24-48 h after labor. The main assessment methods were the following psychometric scales: Beck Depression Inventory (BDI), Edinburgh Postnatal Depression Scale (EPDS) and Athens Insomnia Scale (AIS). Serum estradiol levels were measured using ELISA assay. Women who developed postpartum insomnia significantly more often reported insomnia during pregnancy (P = 0.001), were more likely to have suffered from depression in the past (P = 0.007) and had significantly higher BDI (P = 0.002) and EPDS (P = 0.048) scores. Our study demonstrated no significant association between Restless Legs Syndrome (RLS) during pregnancy and postpartum insomnia. The groups of women with and without postpartum RLS showed no significant differences in the incidence of postpartum insomnia. No significant differences in estradiol levels were observed in women with and without postpartum insomnia. The study showed the following factors to play a major role in development of postpartum insomnia: an increase in Beck Depression Inventory score, a history of depression and a history of insomnia during pregnancy.

Zinc in the Monoaminergic Theory of Depression: Its Relationship to Neural Plasticity.

Preclinical and clinical studies have demonstrated that zinc possesses antidepressant properties and that it may augment the therapy with conventional, that is, monoamine-based, antidepressants. In this review we aim to discuss the role of zinc in the pathophysiology and treatment of depression with regard to the monoamine hypothesis of the disease. Particular attention will be paid to the recently described zinc-sensing GPR39 receptor as well as aspects of zinc deficiency. Furthermore, an attempt will be made to give a possible explanation of the mechanisms by which zinc interacts with the monoamine system in the context of depression and neural plasticity.

Anxiety and depression in women undergoing infertility treatment.

Infertility is a significant problem for millions of couples. Recently more attention is being paid to the relationship between infertility treatment with the use of Assisted Reproductive Techniques and the presence of mental disturbances, of which anxiety and depression are the most common. We present a review of recent studies evaluating the influence of anxiety and depression on fertility treatment outcomes and the effect of Assisted Reproductive Techniques treatment on the presence of anxiety and depression among women. The studies show conflicting results concerning the effect of anxiety on Assisted Reproductive Techniques treatment outcomes, but most reveal that Assisted Reproductive Techniques treatment leads to an increased level of anxiety, especially in cases of treatment failure and longer durations of treatment. Most studies do not show a relationship between depression and Assisted Reproductive Techniques treatment outcomes, but it seems that severe depression can lead to lower rates of pregnancy during infertility treatment with Assisted Reproductive Techniques. Moreover, women who become pregnant after Assisted Reproductive Techniques treatment seem to have an increased risk of depression in later life.

The usefulness of monitored therapy using Clozapine concentration in the blood serum for determining drug dose in Polish schizophrenic patients.

BACKGROUND: The aim of the study is to evaluate the advisability of systematic monitoring of clozapine (CLO) concentration in serum during treatment of schizophrenia in Polish psychiatric patients. METHOD: The concentration of CLO and its metabolites: norclozapine (NCLO) and clozapine N-oxide (CLO-NO) in serum obtained from 107 patients suffering from schizophrenia was determined by high performance liquid chromatography (HPLC) method. There were two groups of patients. In the first group of patients (n=95) the concentration of drug and its metabolites was determined by one-time testing. Correlations were tested using the test statistics. In the second group of patients (n=12), 51 samples of serum were provided by the same patient in different time spans (from 6days to 14 months after the beginning of the treatment). RESULTS: Concentrations of CLO and its metabolites in blood serum do not always show a linear dependence on the applied dose for individual patients. CONCLUSION: The high volatility of CLO concentrations in blood serum of patients treated with identical doses of the drug confirmed the validity of the monitored therapy.

Magnesium in depression.

Magnesium is one of the most essential mineral in the human body, connected with brain biochemistry and the fluidity of neuronal membrane. A variety of neuromuscular and psychiatric symptoms, including different types of depression, was observed in magnesium deficiency. Plasma/serum magnesium levels do not seem to be the appropriate indicators of depressive disorders, since ambiguous outcomes, depending on the study, were obtained. The emergence of a new approach to magnesium compounds in medical practice has been seen. Apart from being administered as components of dietary supplements, they are also perceived as the effective agents in treatment of migraine, alcoholism, asthma, heart diseases, arrhythmias, renal calcium stones, premenstrual tension syndrome etc. Magnesium preparations have an essential place in homeopathy as a remedy for a range of mental health problems. Mechanisms of antidepressant action of magnesium are not fully understood yet. Most probably, magnesium influences several systems associated with development of depression. The first information on the beneficial effect of magnesium sulfate given hypodermically to patients with agitated depression was published almost 100 years ago. Numerous pre-clinical and clinical studies confirmed the initial observations as well as demonstrated the beneficial safety profile of magnesium supplementation. Thus, magnesium preparations seem to be a valuable addition to the pharmacological armamentarium for management of depression.

Vitamin D and the central nervous system.

Vitamin D is formed in human epithelial cells via photochemical synthesis and is also acquired from dietary sources. The so-called classical effect of this vitamin involves the regulation of calcium homeostasis and bone metabolism. Apart from this, non-classical effects of vitamin D have recently gained renewed attention. One important yet little known of the numerous functions of vitamin D is the regulation of nervous system development and function. The neuroprotective effect of vitamin D is associated with its influence on neurotrophin production and release, neuromediator synthesis, intracellular calcium homeostasis, and prevention of oxidative damage to nervous tissue. Clinical studies suggest that vitamin D deficiency may lead to an increased risk of disease of the central nervous system (CNS), particularly schizophrenia and multiple sclerosis. Adequate intake of vitamin D during pregnancy and the neonatal period seems to be crucial in terms of prevention of these diseases.

Serum cortisol concentration in patients with major depression after treatment with fluoxetine.

Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis and elevated cortisol levels is characteristic of the pathophysiology of major depressive disorder (MDD). The aim of this study was to determine whether increased plasma cortisol levels appear in patients with major depression and if effective antidepressant treatment by fluoxetine leads to regulation of cortisol level. This aim was realized by describing and validation of methods of determining fluoxetine and cortisol in serum and searching for correlation between their concentrations in patients with endogenous depression, the therapeutic effect as assessed in Hamilton Depression Rating Scale (HDRS), age and sex of patients. Plasma cortisol and fluoxetine levels were measured using high performance liquid chromatography (HPLC) methods with applying Shimadzu chromatograph with UV detection. Plasma cortisol and fluoxetine levels were measured at time zero (before therapy) and after 6h, 24h, 2, 4, 6 and 8 weeks of fluoxetine administration in patients with major depression qualified for therapeutic drug monitoring (TDM). The study included 21 patients (14 women, 7 men; mean age 29-75 years) and 24 healthy comparison subjects. The patients had a mean score on the 21-item HDRS. As the effect of fluoxetine administration the decrease of the level of cortisol was observed in patients who responded to the therapy (the reduction of points in HDRS scale in at least 50%). The validation parameters of HPLC method of fluoxetine and cortisol determination indicate the possibility of applying them for determination of both: the level of concentration of the drug in therapeutic drug monitoring and the level of cortisol in serum of patients with endogenous depression.

Serum cortisol concentration in patients with major depression after treatment with clomipramine.

Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis and elevated cortisol (CORT) levels are characteristics of the pathophysiology of major depressive disorder. The aim of this study was to determine whether increased plasma CORT levels appear in patients with major depression and if effective antidepressant treatment by clomipramine (CLO) leads to regulation of CORT level. Plasma CORT levels were measured using high performance liquid chromatography (HPLC) methods in patients with major depression at time zero (before therapy) and after 3 h, 24 h, 4, 6 and 8 weeks of CLO administration. The study included 17 patients (12 women, 5 men; mean age 54.5 years, SD =12.3) and 21 healthy comparison subjects. The patients had a mean score on the 21-item Hamilton Depression Rating Scale (HDRS) of 26.8 (range 22-35). Eight of the patients with major depression recruited for the study showed a 46% increase in CORT concentration compared to the established standard. In 13 patients treated with CLO, serum CLO levels reached a therapeutic range. In recovered depressed patients, antidepressant treatment significantly reduced HDRS scores from the 6th week of treatment. A drop in plasma CORT levels in recovered depressed subjects occurred 0 to 6 weeks after CLO treatment (n = 5, p < 0.046). However, neither subject group exhibited any definitive markers of CORT secretion. In the population studied, patients had distinct profiles of HPA axis dysregulation. Finding a linear correlation between lower CORT secretion and therapeutic plasma CLO levels is the first aim of monitored therapy and may be important for understanding the pathophysiology of major depressive disorder.

Antidepressant activity of zinc and magnesium in view of the current hypotheses of antidepressant action.

The clinical efficacy of current antidepressant therapies is unsatisfactory; antidepressants induce a variety of unwanted effects, and, moreover, their therapeutic mechanism is not clearly understood. Thus, a search for better and safer agents is continuously in progress. Recently, studies have demonstrated that zinc and magnesium possess antidepressant properties. Zinc and magnesium exhibit antidepressant-like activity in a variety of tests and models in laboratory animals. They are active in forced swim and tail suspension tests in mice and rats, and, furthermore, they enhance the activity of conventional antidepressants (e.g., imipramine and citalopram). Zinc demonstrates activity in the olfactory bulbectomy, chronic mild and chronic unpredictable stress models in rats, while magnesium is active in stress-induced depression-like behavior in mice. Clinical studies demonstrate that the efficacy of pharmacotherapy is enhanced by supplementation with zinc and magnesium. The antidepressant mechanisms of zinc and magnesium are discussed in the context of glutamate, brain-derived neurotrophic factor (BDNF) and glycogen synthase kinase-3 (GSK-3) hypotheses. All the available data indicate the importance of zinc and magnesium homeostasis in the psychopathology and therapy of affective disorders.