Single arketamine in treatment resistant depression: Presentation of 3 cases with regard to sick-leave duration.

BACKGROUND: Ketamine is the prototypal rapid-acting antidepressant (RAAD) for TRD with approved indication for esketamine-nasal spray (ESK-NS). Distinctly, arketamine (R-KET) demonstrates enhanced antidepressant effects and neuroplasticity changes compared to esketamine, with fewer dissociative side effects and abuse potential. This study focuses on R-ketamine's therapeutic implications, safety, and tolerability in TRD treatment. METHODS: We report on a year-long follow-up of three TRD patients post-single IV R-KET administration. The study, conducted under the clinical trial PCN-101 (NCT05414422), observed these subjects for healthcare resource utilization and social support system impact. Participants, adults diagnosed with recurrent major depressive disorder without psychotic features, were observed in a year-long follow-up period for safety. RESULTS: Case analyses revealed significant symptom reduction and improved social and vocational functioning, with reduced sick leaves and hospitalizations post-treatment. However, one case developed a substance use disorder, underscoring the need for vigilant monitoring. The study highlights R-KET's transformative potential in managing depression, indicating a shift in TRD treatment strategies towards early, aggressive interventions. CONCLUSIONS: Despite promising findings, the study faces limitations due to its small sample size, lack of randomization, and potential observational design biases. The results, while aligning with existing ketamine research, require cautious interpretation and warrant further investigation with larger, more robust studies. This exploration of R-KET's role in home-based TRD treatment opens avenues for future research, particularly focusing on its long-term effectiveness and safety in diverse patient populations. This study is registered in clinicaltrials.gov: NCT06232291.

Exploring the Relationship between Mood Disorders and Coexisting Health Conditions: The Focus on Nutraceuticals.

Major depressive disorder and bipolar disorder are the leading causes of global disability. Approximately 50% of patients fail to attain remission, prompting a pronounced focus on the significance of dietary patterns and specific nutrients within the pathophysiology of mood disorders. The connection between chronic diseases and mood disorders follows a bidirectional pattern: physical ailments are interrelated with affective disorders, and, concurrently, mood symptoms often precede chronic diseases and have the potential to worsen their prognosis. Nutraceuticals affect factors that could potentially impact the onset of mood disorders: monoamines and brain-derived neurotrophic factor (BDNF) concentrations, neuroinflammation, oxidative stress, and sleep quality. Furthermore, mood disorders rarely manifest in isolation. Typically, such patients concurrently experience other mental disorders or somatic comorbidities: obesity, hypertension, diabetes, polycystic ovary syndrome (PCOS), etc., where providing nutritional support is also pertinent. To optimize the therapeutic approach for individuals with mood disorders, incorporating nutritional support may not solely ameliorate symptoms stemming directly from the mental condition, but also indirectly through interventions targeting comorbidities.

Are the self-administered questionnaires appropriate to uncover undiagnosed depression among people with epilepsy?

Letter to the Editor.

Case Report: Repeated Series of Ketamine Infusions in Patients With Treatment-Resistant Depression: Presentation of Five Cases.

Purpose: Approximately 30% of patients with major depressive disorder (MDD) are treatment resistant. There is an unquestionable need for new treatment strategies. Subanesthetic doses of intravenous (IV) ketamine have a rapid antidepressant effect in treatment-resistant depression (TRD). This paper describes the efficacy of repeated series of intravenous ketamine infusions as an add-on treatment in five TRD inpatients. Methods: Eligible patients aged 43-63 were given eight ketamine infusions as an add-on treatment for patients with MDD. The subjects have readministered the intervention due to worsening depressive symptoms. Results: Of the five inpatients given ketamine as a series of eight infusions, one underwent three, and four had two treatment series. Four patients achieved remission after first series and three after the second series of ketamine infusions. The adverse reactions were mild and transient with no sequelae. Limitations: Presented case series applies to short-term intervention with IV ketamine as an add-on therapy. The results cannot be generalized to the long-term maintenance treatment nor other ketamine formulations as well as different administration schedules and dosing. Conclusions: This case series showed efficacy and safety of the repeated series of IV ketamine treatment in TRD in MDD and bipolar disorder type I. The subsequent interventions were safe and observed adverse events were mild and transient. Interestingly, the IV ketamine treatment at successive administrations seems to alter the major depression severity of the next affective episode. There is a critical need for further research regarding IV ketamine treatment effectiveness and long-term safety in future studies.

Magnesium in Ketamine Administration in Treatment-Resistant Depression.

Relationship between depression and magnesium levels is reported. This observational study examined whether serum magnesium concentration change over time of ketamine treatment course, also whether association between magnesium concentrations and treatment response measured with Montgomery-Åsberg Depression Rating Scale (MADRS) score occurs. Moreover, interlink between changes in Young Mania Rating Scale (YMRS) score, somatic comorbidities, and magnesium concentration was studied. Inpatients with major depressive disorder or bipolar disorder were rated weekly by clinician using MADRS and YMRS. Magnesium levels assessments were carried out weekly, before start of ketamine treatment and then every second infusion and one week after last ketamine infusion. The concentration of Mg2+ ions differs depending on the measurement. The Mg2+ concentration in pre-measurement was significantly higher than in measurement after five infusions (p = 0.031) and after seven infusions (p = 0.003). No significant correlation was observed between changes in magnesium serum levels and MADRS or YMRS. The concentration of Mg2+ ion in course of the treatment was not associated with somatic comorbidities. The study supports data for role of magnesium in treatment-resistant depression, particularly related to ketamine treatment, but provides no clear evidence of straightforward association between magnesium serum concentration and treatment response or comorbidity.

Copper and anti-anhedonic effect of ketamine in treatment-resistant depression.

Treatment-resistant depression (TRD) remains one of the major psychiatric challenges worldwide. Search for non-monoaminergic agents, possibly effective in treatment of TRD is of prime importance. One of those agents is ketamine - a dissociative, anesthetic drug exhibiting a fast antidepressant action in patients with TRD. Concurrently, anhedonia appears to be significant symptom domain with far-reaching impact on course of treatment. There is data demonstrating that abnormal copper levels might be associated with symptoms of depression. As there is common denominator in ketamine and copper role in neurotransmission this paper is to explore the associations of blood copper levels and psychometric measures in patients with TRD in course of major depressive disorder (MDD) and bipolar disorder (BP), focusing on anhedonia measured with Snaith-Hamilton Pleasure Scale (SHAPS) score.

Copper Concentrations in Ketamine Therapy for Treatment-Resistant Depression.

Changes in serum copper concentration are observed in patients with depressive symptoms. Unmet needs in contemporary antidepressant treatment have increased interest in non-monoaminergic antidepressants, such as ketamine, an anaesthetic drug that has demonstrated a rapid antidepressant effect in patients with treatment-resistant depression (TRD). The purpose of this study was to examine whether serum copper concentrations change during ketamine treatment and whether there is an association between the copper concentrations and treatment response measured using psychometric scale scores. Moreover, the interlink between somatic comorbidities and copper concentration was studied. Patients with major depressive disorder or bipolar disorder were rated weekly by a clinician using the Montgomery-Asberg Depression Rating Scale (MADRS) and Young Mania Rating Scale (YMRS). Copper level assessments were carried out weekly before the start of ketamine treatment and then after every second infusion and one week after the last ketamine infusion. The serum concentration of copper before ketamine treatment was significantly higher than that after the fifth infusion (p = 0.016), and the serum concentration after the treatment was significantly higher than that after the fifth infusion (p = 0.048). No significant correlations between changes in the copper serum concentrations and MADRS or YMRS were found. The serum copper level was not associated with somatic comorbidities during the course of treatment. This study provides data on the role of copper in short-term intravenous ketamine treatment in TRD, although no clear evidence of a connection between the copper level and treatment response was found.

Affective Switch Associated With Oral, Low Dose Ketamine Treatment in a Patient With Treatment Resistant Bipolar I Depression. Case Report and Literature Review.

There is a growing evidence for the rapid and robust antidepressive effect of ketamine in unipolar and bipolar treatment resistant depression although evidence for the risk of affective switch is still limited. This case presents bipolar I disorder patient with treatment resistant depressive episode experiencing a switch to manic episode with mixed features shortly after receiving eight subanaesthetic doses of oral ketamine as an add-on treatment preceded by 2-day period of manic symptoms.

Antipsychotic drugs in epilepsy.

The prevalence of various psychiatric disorders in people with epilepsy is high, with psychoses affecting 2-9% of patients. Antipsychotic drugs have been identified as increasing the risk of epileptic seizures. For first-generation antipsychotics such a risk appears to be relatively low, with the exception of chlorpromazine. Among second-generation antipsychotics, clozapine use carries the highest risk of seizure induction, while risperidone, quetiapine, amisulpride, and aripiprazole seem to pose a significantly lower risk. The incidence of an increased number of seizures is linked to the elevated blood plasma level effect of antipsychotics. To diminish the risk of seizures, it is important to start with a small dose of antipsychotic drug, to titrate slowly, to monitor serum levels of prescribed drugs, and to keep the drug at the minimal effective dose.

The immunomodulatory effect of ketamine in depression.

Major depression is one of the most frequent psychiatric conditions. Despite many available treatment methods, more than 30% of patients do not achieve remission, even after trying several antidepressants and augmentation strategies. S-enantiomer of ketamine, well-known anesthetic and analgesic, has been recently approved by Food and Drug Administration in the intranasal form as a new generation antidepressant. However, the mechanism in which ketamine reduces depressive symptoms in treatment-resistant depression patients is still not completely understood. There are several theories explaining how ketamine might reduce depressive symptoms, which have been described in detail; one of them is immunomodulatory effect of ketamine, according to the inflammatory theory of depression. In the review authors present and summarize studies showing ketamine effect on human immune system ex vivo and in vitro, including changes in cytokine levels, number, ratio and activity of various immune cell population and the correlation with clinical improvement in depressive symptoms. Most of the results confirm the anti-inflammatory effect of ketamine. There are only a few studies in the population of patients suffering from depression receiving ketamine, focused on correlation between immunological changes and clinical outcome of the therapy; further studies of that area are neccesary for understanding the immunomodulatory effect of ketamine in depression.

Suicidality in treatment resistant depression: perspective for ketamine use.

Suicidal ideations or attempts in patients with major depressive disorder (MDD) are emergent conditions that require immediate treatment. Numerous therapeutic interventions to reduce suicide risk in psychiatric disorders are effective in long-term suicide prevention, but there is necessity of sufficient, rapid pharmacological treatment of suicidal risk in MDD. Ketamine, an N-methyl-D-aspartate (NMDA) antagonist, has been reported to have rapid antidepressant effect. Depressive symptoms, anxiety, hopelessness, suicidal ideation had decreased within hours after ketamine infusion. Ketamine's rapid symptoms relief and reduction of suicide thoughts has aroused growing interests in psychiatric association.

Role of copper and ketamine in major depressive disorder - an update.

Major depressive disorder is one of the most important psychiatric issues worldwide, with important prevalence of treatment-resistant depression (TRD). Non-monoaminergic agents are currently in the spotlight. Objective was to explore for information about mechanisms of action of ketamine, its connections with copper and possible importance for TRD treatment. There are at least few possible pathways for ketamine action in depression in which copper and other divalent ions may show a vital role. There is urgent need for more studies to gather information about correlation between ketamine, copper and antidepressive features of these agents.

Magnesium and ketamine in the treatment of depression.

Depression affects over 121 million people annually worldwide. Relatively low remission rates among depressive patients enforce the search for new therapeutic solutions and an urgent need to develop faster-acting antidepressants with a different mechanism of action occurs. The pathomechanism of depression postulated by the monoamine hypothesis is limited. The results of abnormalities in glutamate and γ-aminobutyric acid (GABA) systems in the brains of people with mood disorders allowed to develop new theories regarding pathophysiology of these disorders. Glutamatergic transmission is influenced by magnesium and ketamine through glutamatergic N-methyl-D-aspartate receptor (NMDAR) antagonistic effects. Magnesium and ketamine have a common mechanism of action in the treatment of depression: an increase in GluN2B (NMDAR subunit) expression is related to the administration of both of the agents, as well as inhibition of phosphorylation of eEF2 (eukaryotic elongation factor 2) in cell culture and increase of the expression of BDNF in the hippocampus. Combination of ketamine and magnesium in a normal magnesium level presents a superadditive effect in depression treatment. Analysed substances affect the GABAergic system and have anti-inflammatory effects, which is correlated with their antidepressant effect. The synergistic interaction between the pharmacodynamic activity of magnesium and ketamine may be of particular importance for patients with mood disorders. Further research is needed to determine the relationship between magnesium levels and ketamine treatment response mainly in the attempt to establish if the magnesium supplementation can change ketamine treatment response time or present superadditive effect.

Efficacy of Ketamine in bipolar depression: focus on anhedonia.

Bipolar depression (BD) is among the most severe psychiatric disorders. A significant number of patients do not achieve an entirely symptom-free state and experience residual sub-syndromal depression. Most of the treatment options approved for bipolar depression give no rapid symptom improvement. Ketamine is an anaesthetic medication that acts as an antagonist of the NMDA receptor and has antidepressant potential. Due to its unique way of action, ketamine seems to be crucial for the treatment of anhedonia. This review paper aims to provide an overview of the efficacy of ketamine infusions in bipolar depression with a focus on anhedonia Literature suggests that intravenous ketamine 0.5 mg/kg over 40 min weekly could be useful in the treatment of bipolar depression with prominent anhedonia, but there is still a small number of studies that examine the efficacy of ketamine infusions in BD. In conclusion, ketamine should be considered as a valuable treatment option for patients with BD and anhedonia.

Ketamine and magnesium common pathway of antidepressant action.

Depression is one of the major causes of disability worldwide. A proportion of adults with major depression fail to achieve remission with first-line treatment. Magnesium influences the neurotransmission involved in emotional processes, such as the serotonergic, noradrenergic, dopaminergic, GABAergic and glutamatergic systems. It has been reported that the mechanism of antidepressants' action is involved in the glutamatergic system. Theories about the role of magnesium ions in pathophysiology of major depressive disorder include blocking the glutamatergic N-methyl-D-aspartate receptor (NMDAR). Ketamine, NMDAR antagonist, was found to promote fast-acting antidepressant and antisuicidal effects. Magnesium and ketamine seem to be involved in key mechanisms of the major depression pathophysiology. The evidence in the paper discussed may indicate the synergistic interaction between magnesium and ketamine pharmacodynamic activity being of particular importance in mood disorders.

Role of copper in depression. Relationship with ketamine treatment.

Depression is one of the most common psychiatric issues with a proportion of adults with major depressive disorder who fail to achieve remission with index pharmacological treatment. There are unmet needs in ADT focus on non-monoaminergic agents. Accumulating evidence suggests that the N-Methyl-d-aspartate receptor (NMDAR) plays an important role in the neurobiology and treatment of major depressive disorder. The role of copper ions in pathogenesis and treatment of depression is not fully clarified, however interaction between copper and NMDAR is of prime importance. Release of copper ions inhibits NMDAR and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor function thus protects neurons from glutamatergic excitotoxity. Abnormalities in glutamatergic transmission are the key of glutamate hypothesis of depression. Some authors revealed that NMDARs are also regulated by cellular prion protein (PrPC) and indicated that interactions of copper, glycine and NMDARs subunits are vital for the regulation of the receptor. As NMDAR antagonist ketamine is known to produce rapid antidepressive effect, observation of copper serum levels in patients treated with ketamine may provide important information about connections between NMDAR antagonistic agents and trace elements antagonistic to that receptor. It is necessary to carry out further studies related to copper and ketamine in depression treatment.

Antidepressants in epilepsy.

People with epilepsy (PWE) frequently suffer from comorbid mood and anxiety disorders. Depression is one of the major psychiatric comorbidities having a negative impact on the quality of life in people with epilepsy. A review of the literature indicates that the majority of antidepressant-related seizures have been associated with either ultra-high doses or overdosing and, generally, the risk of antidepressant-associated seizures is low. Correspondingly, there is some evidence indicating that antidepressants of most widely used groups may additionally lower the risk of triggering seizures. Four antidepressants are not recommended for patients with epilepsy, i.e.: amoxapine, bupropion, clomipramine and maprotiline. Clinicians applying first line of depression treatment in patients with epilepsy should consider use of SSRIs or SNRIs, particularly sertraline, citalopram, mirtazapine, reboxetine, paroxetine, fluoxetine, escitalopram, fluvoxamine, venlafaxine, duloxetine. Implementation of anticonvulsive drugs in depressed patients should include valproate, carbamazepine, lamotrigine, gabapentin, pregabalin. The paper reviews the evidence for the clinical use of antidepressants in PWE.