Advances in Mood Disorder Pharmacotherapy: Evaluating New Antipsychotics and Mood Stabilizers for Bipolar Disorder and Schizophrenia.

This article provides a narrative review of recent developments in mood-stabilizing drugs, considering their mechanism of action, efficacy, safety, and therapeutic potential in the treatment of mood disorders, particularly bipolar disorder and schizophrenia. The review focuses on the mechanism and clinical aspects of second-generation antipsychotic medications; aripiprazole, classified as a third-generation antipsychotic medication; lamotrigine, as a representative of antiepileptic drugs; and lurasidone, a novel second-generation antipsychotic medication. Moreover, the article refers to one of the newest and most highly effective normothymic drugs, cariprazine. The potential of new mood stabilizer candidates lumateperone and brexpiprazole is also presented. Covered topics include the clinical efficacy of new drugs in reducing manic and depressive symptoms during acute episodes, as well as their role in preventing relapse. In addition, we analyzed the incidence of adverse effects of each drug. Many of the new drugs have strong potential to be beneficial and safe in cases of many comorbidities, as they do not cause many adverse effects and do not require high doses of use. The results underscore the importance of ongoing and future research to better understand the action and efficacy of these mood stabilizers and their implications in the treatment of mood disorders, aiming to achieve euthymia and improve the quality of life of affected patients. In this article, we aim to review current drug treatments for the management of mood disorders, including bipolar disorder and schizophrenia.

Investigating the association of the effect of genetically proxied PCSK9i with mood disorders using cis-pQTLs: A drug-target Mendelian randomization study.

PCSK9-inhibitors (PCSK9i) are new drugs recently approved to lower LDL-cholesterol levels. However, due to the lack of long-term clinical data, the potential adverse effects of long-term use are still unknown. The PCSK9 genetic locus has been recently implicated in mood disorders and hence we wanted to assess if the effect of PCSK9i that block the PCSK9 protein can lead to an increase in the incidence of mood disorders. We used genetically-reduced PCSK9 protein levels (pQTLs) in plasma, serum, cerebrospinal fluid as a proxy for the effect of PCSK9i. We performed Mendelian randomization analyses using PCSK9 levels as exposure and mood disorder traits major depressive disorder, mood instability, and neuroticism score as outcomes. We find no association of PCSK9 levels with mood disorder traits in serum, plasma, and cerebrospinal fluid. We can conclude that genetically proxied on-target effect of pharmacological PCSK9 inhibition is unlikely to contribute to mood disorders.

Clinical experience with parenteral trazodone in mood disorders: A literature review. / Doswiadczenia kliniczne z trazodonem stosowanym droga pozajelitowa w zaburzeniach nastroju: przeglad literatury.

Trazodone is a serotonin antagonist/reuptake inhibitor, approved for treating major depressive disorder (MDD). Oral formulations are widely studied and marketed in several countries worldwide while there is little evidence to support use of parenteral formulation. Our narrative review summarizes pharmacological properties and clinical data concerning use of parenteral trazodone in mood disorders. PubMed and Web of Science were used to identify the most relevant literature. The main evidence concerns four studies evaluating efficacy in major depressive disorder and indicates that trazodone was well tolerated and effective. Off-label use in agitation associated with bipolar disorder is also reported in three studies, although prescription of concomitant treatment, as a confounding factor, may have influenced outcome measures. The limited available evidence supports parenteral trazodone use in major depressive disorder and suggests that trazodone is a suitable option in patients at high risk of treatment-emergent mania (TEM).

FDA-approved cannabidiol [Epidiolex®] alleviates Gulf War Illness-linked cognitive and mood dysfunction, hyperalgesia, neuroinflammatory signaling, and declined neurogenesis.

BACKGROUND: Chronic Gulf War Illness (GWI) is characterized by cognitive and mood impairments, as well as persistent neuroinflammation and oxidative stress. This study aimed to investigate the efficacy of Epidiolex®, a Food and Drug Administration (FDA)-approved cannabidiol (CBD), in improving brain function in a rat model of chronic GWI. METHODS: Six months after exposure to low doses of GWI-related chemicals [pyridostigmine bromide, N,N-diethyl-meta-toluamide (DEET), and permethrin (PER)] along with moderate stress, rats with chronic GWI were administered either vehicle (VEH) or CBD (20 mg/kg, oral) for 16 weeks. Neurobehavioral tests were conducted on 11 weeks after treatment initiation to evaluate the performance of rats in tasks related to associative recognition memory, object location memory, pattern separation, and sucrose preference. The effect of CBD on hyperalgesia was also examined. The brain tissues were processed for immunohistochemical and molecular studies following behavioral tests. RESULTS: GWI rats treated with VEH exhibited impairments in all cognitive tasks and anhedonia, whereas CBD-treated GWI rats showed improvements in all cognitive tasks and no anhedonia. Additionally, CBD treatment alleviated hyperalgesia in GWI rats. Analysis of hippocampal tissues from VEH-treated rats revealed astrocyte hypertrophy and increased percentages of activated microglia presenting NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) complexes as well as elevated levels of proteins involved in NLRP3 inflammasome activation and Janus kinase/signal transducers and activators of the transcription (JAK/STAT) signaling. Furthermore, there were increased concentrations of proinflammatory and oxidative stress markers along with decreased neurogenesis. In contrast, the hippocampus from CBD-treated GWI rats displayed reduced levels of proteins mediating the activation of NLRP3 inflammasomes and JAK/STAT signaling, normalized concentrations of proinflammatory cytokines and oxidative stress markers, and improved neurogenesis. Notably, CBD treatment did not alter the concentration of endogenous cannabinoid anandamide in the hippocampus. CONCLUSIONS: The use of an FDA-approved CBD (Epidiolex®) has been shown to effectively alleviate cognitive and mood impairments as well as hyperalgesia associated with chronic GWI. Importantly, the improvements observed in rats with chronic GWI in this study were attributed to the ability of CBD to significantly suppress signaling pathways that perpetuate chronic neuroinflammation.

Psychotropic Medications Promote Time-Dependent Reduction of Suicidal Ideation in Mood Disorder: A Prospective Cohort Study.

BACKGROUND: Despite a plethora of research on the topic, there is still no solid evidence that pharmacological treatment actually reduces the risk of suicide in patients with mental illness. In this study, we aimed to assess the effect of psychotropic medications on suicidal ideation in patients with major depressive disorder (MDD) and bipolar disorder (BPD) in two age groups: less than 25 years and 25 years and older. METHODS: We analyzed 312 patients with mood disorders with current suicidal thoughts or recent suicide attempts. We followed the participants from baseline for 6 months and assessed changes in suicidal ideation with Columbia-Suicide Severity Rating Scale (C-SSRS). The effect of psychotropic drug administration on suicidal ideation over time was analyzed using a linear mixed model. RESULTS: In patients aged 25 years and older with mood disorders, suicidal ideation was more severe when using psychotropic drugs than when not using them. However, suicidal ideation decreased rapidly over time. The time-dependent reduction in suicidal ideation was accelerated when using antidepressants and sedatives/hypnotics in adult MDD, and when using mood stabilizers in adult BPD. However, this effect was not observed in participants aged less than 25 years. CONCLUSION: Adequate psychotropic medication may reduce suicidal ideation in patients with mood disorders aged 25 years and older. Additional research on psychotropic drugs is needed to effectively reduce the risk of suicide among children and adolescents with mood disorders.

Newer Treatments for Mood and Anxiety Disorders.

For more than 20 years, the mainstay of pharmacologic treatment for depression and anxiety disorders has been serotonin reuptake inhibitors and selective serotonin and norepinephrine reuptake inhibitors. There are newer medications, many with novel mechanisms of action, that have come to market; however, first-line treatments remain the same. There are now more robust data on the use of various augmentation agents in the treatment of major depressive disorder providing better recommendations for use by the primary care provider. Data to support the use of psychedelic-assisted psychotherapy in the treatment of mood and anxiety disorders are not robust enough to recommend generalized use at this time.

Lysophosphatidic Acid (LPA) and Its Receptors in Mood Regulation: A Systematic Review of the Molecular Mechanisms and Therapeutic Potential.

Mood disorders affect over 300 million individuals worldwide, often characterized by their chronic and refractory nature, posing significant threats to patient life. There has been a notable increase in mood disorders among American adolescents and young adults, with a rising number of suicide attempts and fatalities, highlighting a growing association between mood disorders and suicidal outcomes. Dysregulation within the neuroimmune-endocrine system is now recognized as one of the fundamental biological mechanisms underlying mood and mood disorders. Lysophosphatidic acid (LPA), a novel mediator of mood behavior, induces anxiety-like and depression-like phenotypes through its receptors LPA1 and LPA5, regulating synaptic neurotransmission and plasticity. Consequently, LPA has garnered substantial interest in the study of mood regulation. This study aimed to elucidate the molecular mechanisms of lysophosphatidic acid and its receptors, along with LPA receptor ligands, in mood regulation and to explore their potential therapeutic efficacy in treating mood disorders. A comprehensive literature search was conducted using the PubMed and Web of Science databases, identifying 208 articles through keyword searches up to June 2024. After excluding duplicates, irrelevant publications, and those restricted by open access limitations, 21 scientific papers were included in this review. The findings indicate that LPA/LPA receptor modulation could be beneficial in treating mood disorders, suggesting that pharmacological agents or gintonin, an extract from ginseng, may serve as effective therapeutic strategies. This study opens new avenues for future research into how lysophosphatidic acid and its receptors, as well as lysophosphatidic acid receptor ligands, influence emotional behavior in animals and humans.

Sixty years of recurrence prevention in mood disorders. / Szescdziesiat lat profilaktyki nawrotów chorób afektywnych.

This year, we observe sixty's anniversary of the article by a British psychiatrist, Geoffrey Hartigan, demonstrating, for the first time, the possibility of preventing of the recurrence of mood disorders by using lithium salts. Herein, a history of prevention of recurrences of mood disorders both worldwide and in Poland will be presented concerning both lithium and other mood-stabilizing drugs. The merit for verifying the prophylactic lithium effect in the 1960-1970s should be given to Danish researchers, Mogens Schou and Poul Baastrup. In Poland, the first paper on prophylactic lithium appeared already in 1971. In the 1970s, French researchers showed prophylactic activity of valproic acid amide, and Japanese researchers - carbamazepine. In the 1980th, studies on valproic acid amide were performed in the 2nd Psychiatric Clinic of the Institute of Psychiatry and Neurology led by Prof. Puzynski. Since the mid-1990s, 2nd generation of mood-stabilizing drugs has been introduced, including some atypical antipsychotics (clozapine, olanzapine, quetiapine, aripiprazole, risperidone) and anticonvulsant drug, lamotrigine, showing prophylactic activity in bipolar mood disorder. The studies on lithium resulted in the identification of factors connected with its prophylactic efficacy as well as the antisuicidal, antiviral, and neuroprotective effects of this drug. From a sixty-year perspective following Hartigan's article, it seems that his pioneering concept on the possibility of pharmacological influence on the course of mood disorders was fully confirmed. Current Polish recommendations on pharmacological prophylaxis of mood disorders were presented in the books "Standardy leczenia niektórych zaburzen psychicznych" and "Psychofarmakologia kliniczna", both published in 2022.

Targeting inflammasome complexes as a novel therapeutic strategy for mood disorders.

INTRODUCTION: Inflammasome complexes, especially NLRP3, have gained great attention as a potential therapeutic target in mood disorders. NLRP3 triggers a caspase 1-dependent release of the inflammatory cytokines IL-1ß and IL-18, and seems to interact with purinergic and kynurenine pathways, all of which are implicated in mood disorders development and progression. AREAS COVERED: Emerging evidence supports NLRP3 inflammasome as a promising pharmacological target for mood disorders. We discussed the available evidence from animal models and human studies and provided a reflection on drawbacks and perspectives for this novel target. EXPERT OPINION: Several studies have supported the involvement of NLRP3 inflammasome in MDD. However, most of the evidence comes from animal models. The role of NLRP3 inflammasome in BD as well as its anti-manic properties is not very clear and requires further exploration. There is evidence of anti-manic effects of P2×R7 antagonists associated with reduction in the brain levels of IL-1ß and TNF-α in a murine model of mania. The involvement of other NLRP3 inflammasome expressing cells besides microglia, like astrocytes, and of other inflammasome complexes in mood disorders also deserves further investigation. Preclinical and clinical characterization of NLRP3 and other inflammasomes in mood disorders is needed before considering translational approaches, including clinical trials.

Arginine vasopressin in mood disorders: A potential biomarker of disease pathology and a target for pharmacologic intervention.

Vasopressin or arginine-vasopressin (AVP) is a neuropeptide molecule known for its antidiuretic effects and serves to regulate plasma osmolality and blood pressure. The existing literature suggests that AVP plays a multifaceted-though less well-known-role in the central nervous system (CNS), particularly in relation to the pathophysiology and treatment of mood disorders. Animal models have demonstrated that AVP is implicated in regulating social cognition, affiliative and prosocial behaviors, and aggression, often in conjunction with oxytocin. In humans, AVP is implicated in mood disorders through its effects on the hypothalamic-pituitary-adrenal (HPA) axis as well as on the serotoninergic and glutamatergic systems. Measuring plasma AVP has yielded interesting but mixed results in mood and stress-related disorders. Recent advances have led to the development of copeptin as a stable and reliable surrogate biomarker for AVP. Another interesting but relatively unexplored issue is the interaction between the osmoregulatory system and mood disorder pathophysiology, given that psychotropic medications often cause dysregulation of AVP receptor expression or signaling that can subsequently lead to clinical syndromes like syndrome of inappropriate diuresis and diabetes insipidus. Finally, pharmaceutical trials of agents that act on V1a and V1b receptor antagonists are still underway. This narrative review summarizes: (1) the neurobiology of the vasopressinergic system in the CNS; (2) the interaction between AVP and the monoaminergic and glutamatergic pathways in the pathophysiology and treatment of mood disorders; (3) the iatrogenic AVP dysregulation caused by psychotropic medications; and (4) the pharmaceutical development of AVP receptor antagonists for the treatment of mood disorders.

Minocycline Abrogates Individual Differences in Nerve Injury-Evoked Affective Disturbances in Male Rats and Prevents Associated Supraspinal Neuroinflammation.

Chronic neuropathic pain precipitates a complex range of affective and behavioural disturbances that differ markedly between individuals. While the reasons for differences in pain-related disability are not well understood, supraspinal neuroimmune interactions are implicated. Minocycline has antidepressant effects in humans and attenuates affective disturbances in rodent models of pain, and acts by reducing neuroinflammation in both the spinal cord and brain. Previous studies, however, tend not to investigate how minocycline modulates individual affective responses to nerve injury, or rely on non-naturalistic behavioural paradigms that fail to capture the complexity of rodent behaviour. We investigated the development and resolution of pain-related affective disturbances in nerve-injured male rats by measuring multiple spontaneous ethological endpoints on a longitudinal naturalistic foraging paradigm, and the effect of chronic oral minocycline administration on these changes. Disrupted foraging behaviours appeared in 22% of nerve-injured rats - termed 'affected' rats - and were present at day 14 but partially resolved by day 21 post-injury. Minocycline completely prevented the emergence of an affected subgroup while only partly attenuating mechanical allodynia, dissociating the relationship between pain and affect. This was associated with a lasting downregulation of ΔFosB expression in ventral hippocampal neurons at day 21 post-injury. Markers of microglia-mediated neuroinflammation were not present by day 21, however proinflammatory microglial polarisation was apparent in the medial prefrontal cortex of affected rats and not in CCI minocycline rats. Individual differences in affective disturbances following nerve injury are therefore temporally related to altered microglial morphology and hippocampal neuronal activation, and are abrogated by minocycline.

The use of prolonged-release melatonin in circadian medicine: a systematic review.

INTRODUCTION: Melatonin, a hormone produced by the pineal gland, regulates the sleep-wake cycle and is effective in restoring biological rhythms. Prolonged-release melatonin (PRM) is designed to mimic the natural physiological pattern of melatonin release. In circadian medicine, PRM can be used to treat sleep and circadian rhythm disorders, as well as numerous organic diseases associated with sleep disorders. EVIDENCE ACQUISITION: This systematic review analyzed 62 studies and adhered to the PRISMA guidelines, examining the effectiveness of PRM in organic pathologies and mental disorders. EVIDENCE SYNTHESIS: The main evidence concerns primary insomnia in subjects over the age of 55, showing significant improvements in sleep quality. In neurodevelopmental disorders, there is evidence of a positive impact on sleep quality and quality of life for patients and their caregivers. PRM shows efficacy in the treatment of sleep disorders in mood disorders, schizophrenia, and neurocognitive disorders, but requires further confirmation. The additional use of PRM is supported for the withdrawal of chronic benzodiazepine therapies. The tolerability and safety of PRM are excellent, with ample evidence supporting the absence of tolerance and dependence. CONCLUSIONS: Overall, PRM in circadian medicine is an effective chronopharmaceutical for restoring the sleep-wake rhythm in patients with insomnia disorder. This efficacy may also extend to sleep disorders associated with mood, neurodevelopmental and neurocognitive disorders, suggesting a further potential role in insomnia associated with various organic diseases.

Prenatal Exposure to Valproic Acid Across Various Indications for Use.

Importance: Teratogenic outcomes associated with valproic acid use represent a substantial concern for persons of childbearing age. Regulatory agencies worldwide have enhanced warnings or implemented risk minimization programs to reduce exposure during pregnancy. Objectives: To determine pregnancy rates during valproic acid use and concomitant contraception use across indications. Design, Setting, and Participants: This retrospective cohort study used data from the Merative MarketScan commercial claims databases from January 1, 2005, to December 31, 2020, to identify female patients aged 12 to 44 years who initiated valproic acid treatment and had continuous insurance enrollment 6 months before initiation and 9 months after treatment end. A treatment episode included consecutive prescription fills that occurred within 7 days from the end of the days' supply of the previous dispensing. Data were analyzed from March 1 to September 10, 2023. Main Outcomes and Measures: Treatment episodes were categorized by inferred indication using diagnoses preceding treatment initiation, including epilepsy, migraine or headache, mood disorders, and unknown or off-label uses. Pregnancy incidence rate ratios (IRRs) were calculated and were adjusted for age and calendar year. Contraceptive use (prescription contraceptives, intrauterine devices, and implants) during treatment was examined. Results: The cohort included 165 772 valproic acid treatment episodes among 69 390 women (mean [SD] age, 29.8 [10.0] years). Mood disorders (42.5%) were the most common indication, followed by migraine or headache (20.1%), with epilepsy playing a minor role (14.9%). Pregnancy incidence rates during valproic acid use remained unchanged, with a rate of 1.74 (95% CI, 1.14-2.53) per 100 person-years in 2005 and a rate of 1.90 (95% CI, 1.16-3.12) per 100 person-years in 2019. Compared with epilepsy, pregnancy rates were more than double for mood disorder (IRR, 2.16 [95% CI, 1.93-2.42]) and migraine or headache (IRR, 2.01 [95% CI, 1.92-2.09]). Few treatment episodes coincided with contraceptive use (37 012 [22.3%]), and oral dosage forms were the most common (27 069 [73.1%]). Conclusions and Relevance: In this cohort study of patients of childbearing age who used valproic acid, pregnancy rates during valproic acid use did not decrease despite enhanced US Food and Drug Administration safety communications, and contraception use remained low. Patients with migraine and mood disorders accounted for the largest proportion of valproic acid use and had the highest pregnancy rates, while patients with epilepsy had the lowest. These findings suggest a need to enhance efforts to mitigate prenatal exposure to valproic acid, especially for indications where the risk of use during pregnancy outweighs the benefit.

[Atypical antipsychotics in the treatment of depression in affective disorders and schizophrenia (using the aripiprazole model)]. / Atipichnye antipsikhotiki pri terapii depressii v ramkakh affektivnykh rasstroistv i shizofrenii (na modeli aripiprazola).

The review discusses aspects of the use of atypical antipsychotics in the treatment of depression in affective disorders and schizophrenia using the model of aripiprazole, a partial agonist of dopamine receptors. According to numerous studies, aripiprazole is the drug of choice for augmentative therapy of major depressive disorder, as well as for relieving and long-term maintenance monotherapy and combination therapy of various affective episodes of bipolar affective disorder and depression in schizophrenia.

Long-term follow-up of participants in ketamine clinical trials for mood disorders.

BACKGROUND: Participants who received ketamine at the NIMH were among the first to receive ketamine for depression in controlled clinical trials, providing a unique opportunity to assess long-term outcomes. This analysis evaluated the relationship between participating in a ketamine clinical trial and subsequent ketamine/esketamine use after leaving the research setting. METHODS: Participants seen within the NIMH Experimental Therapeutics and Pathophysiology Branch from 2002 to 2022 (n = 1000) were contacted for follow-up assessment. Participants reported whether they had used ketamine/esketamine, sought non-prescribed ketamine, attempted suicide, or been psychiatrically hospitalized since discharge. Information regarding their recent depressive symptoms, dissociative symptoms, and hallucinations was also collected. RESULTS: Of the 203 participants in follow-up assessments (55 % female, average time since leaving NIMH = 9.04 years), 52 (25.6 %) had originally received ketamine at the NIMH, and the rest had participated in non-ketamine studies. Individuals who had received ketamine at the NIMH were more likely to have received ketamine/esketamine post-discharge than those who did not receive ketamine at the NIMH (OR = 0.25, p < .001). Participants who reported using ketamine/esketamine post-discharge reported more depressive symptoms than those who had not (p < .001). Receiving ketamine at the NIMH was not associated with differences in suicide attempts, psychiatric hospitalizations, dissociation, hallucinations, or attempt to obtain non-prescribed ketamine. LIMITATIONS: Low follow-up study participation rate; varying time since discharge. CONCLUSIONS: Participants who received ketamine in an NIMH clinical trial were more likely to receive ketamine/esketamine post-discharge, but none reported symptoms indicating abuse. Results underscore the critical need for long-term follow-up of individuals receiving these and other rapid-acting antidepressants. CLINICAL TRIALS IDENTIFIER: NCT04877977.