Schizophrenia is, in part, a cognitive illness. There are no approved medications for cognitive impairments associated with schizophrenia (CIAS) and primary negative symptoms. Cholinergic and glutamatergic systems, alpha-7 nicotinic acetylcholine (α-7nACh) and N-methyl-D-aspartate (NMDA) receptors, kynurenic acid (KYNA), and mismatch negativity have been implicated in the pathophysiology of CIAS and negative symptoms. Galantamine is an acetylcholinesterase inhibitor that is also a positive allosteric modulator at the α4β2 and α7nACh receptors. Memantine is a noncompetitive NMDA receptor antagonist. Galantamine and memantine alone and in combination were effective for cognition in animals and people with Alzheimer’s disease. The objective of this article is to critically dissect the published randomized controlled trials with galantamine and memantine for CIAS to highlight the efficacy signal. These studies may have failed to detect a clinically meaningful efficacy signal due to limitations, methodological issues, and possible medication nonadherence. There is evidence from a small open-label study that the galantamine-memantine combination may be effective for CIAS with kynurenine pathway metabolites as biomarkers to detect the severity of cognitive impairments. Given that there are no available treatments for cognitive impairments and primary negative symptoms in schizophrenia, testing of this “five-pronged strategy” (quintuple hypotheses: dopamine, nicotinic-cholinergic, glutamatergic/NMDA, GABA, and KYNA) is a “low-risk high-gain” approach that could be a major breakthrough in the field. The galantamine-memantine combination has the potential to treat positive, cognitive, and negative symptoms, and targeting the quintuple hypotheses concurrently may lead to a major scientific advancement – from antipsychotic treatment to antischizophrenia treatment.

Parkinson’s disease (PD) is a progressive neurodegenerative disorder that affects over 1% of population over age 60. It is defined by motor and nonmotor symptoms including a spectrum of cognitive impairments known as Parkinson’s disease dementia (PDD). Currently, the only US Food and Drug Administration-approved treatment for PDD is rivastigmine, which inhibits acetylcholinesterase and butyrylcholinesterase increasing the level of acetylcholine in the brain. Due to its limited efficacy and side effect profile, rivastigmine is often not prescribed, leaving patients with no treatment options. PD has several derangements in neurotransmitter pathways (dopaminergic neurons in the nigrostriatal pathway, kynurenine pathway (KP), acetylcholine, α7 nicotinic receptor, and N-methyl-D-aspartate (NMDA) receptors) and rivastigmine is only partially effective as it only targets one pathway. Kynurenic acid (KYNA), a metabolite of tryptophan metabolism, affects the pathophysiology of PDD in multiple ways. Both galantamine (α7 nicotinic receptor) and memantine (antagonist of the NMDA subtype of the glutamate receptor) are KYNA modulators. When used in combination, they target multiple pathways. While randomized controlled trials (RCTs) with each drug alone for PD have failed, the combination of galantamine and memantine has demonstrated a synergistic effect on cognitive enhancement in animal models. It has therapeutic potential that has not been adequately assessed, warranting future randomized controlled trials. In this review, we summarize the KYNA-centric model for PD pathophysiology and discuss how this treatment combination is promising in improving cognitive function in patients with PDD through its action on KYNA.

To examine whether childhood physical and sexual abuse is a significant predictor of suicide risk in veterans. This study was a retrospective chart review of 4,709 patients admitted to a psychiatric ward (August 2004 through July 2014) at the Atlanta Veterans Affairs Medical Center (VAMC). Sociodemographic and clinical data and history of childhood (aged ≤ 18 years) physical and sexual abuse were obtained from the patients' electronic health records. Suicide risk data of patients who attempted and completed suicide were obtained from the Atlanta VAMC suicide high-risk team. Binary logistic regressions with maximum likelihood estimation method were used to examine the association of demographic (age, sex, marital status, race, service) and clinical (psychiatric diagnoses, number of hospital admissions, and length of stay) variables and childhood physical and sexual abuse and type with suicide behavior. The combination of childhood physical and sexual abuse, number of admissions to a psychiatric inpatient unit, and major depressive disorder (MDD) were the best predictors of enhanced suicide risk (P < .001). This combination accounted for 9.9% variance in suicide risk and correctly classified 83% of cases into respective suicide versus nonsuicide risk groups. Additional significant predictors were bipolar disorder (P < .001) and cocaine use disorder (P = .02). Surprisingly, diagnosis of schizophrenia predicted a reduced risk. To our knowledge, this study is the first to shed light on the interaction of childhood physical and sexual abuse and suicide risk in a large cohort of veterans. In the final model, childhood physical and sexual abuse, number of psychiatric admissions, and MDD were the best predictors of increased suicide risk. Schizophrenia was a protective factor in this veteran cohort.

Indian J Psychiatry, Indian Journal of Psychiatry is the official publication of the Indian Psychiatric Society that considers for publication articles in all fields of Psychiatry

Background: Lorazepam is a widely prescribed benzodiazepine that is used to manage anxiety, insomnia, and status epilepticus and is used for pre-anesthetic care as well as several off-label indications including aggression, alcohol withdrawal, panic disorder, chemotherapy-associated anticipatory nausea, and catatonia. Recent increases in demand, manufacturing changes, and quality control issues have resulted in a shortage of injectable and oral lorazepam, prompting clinicians to use alternatives. One such alternative is midazolam, a drug that has been used primarily in the intensive care unit and anesthesia settings. Procedures: This article examines the significant pharmacologic differences between lorazepam and midazolam. In addition, this article provides dosage guidelines based on the current scientific knowledge and recommendations for conversion equivalencies. Results: The clinical preference for lorazepam can be attributed to its simpler metabolism with no active metabolites, better suitability for patients with less severe hepatic and renal impairment, less risk of adverse reactions, fewer drug-drug interactions, and greater desirability for special populations. In periods of shortages, midazolam has been shown to be effective for a number of off-label uses. To manage conditions that have not been extensively studied, clinicians may opt to use conversion equivalencies, with the caveat that guidelines may vary greatly between institutions and online sources; therefore, it would be best to start low and titrate slowly. Conclusions: Our goal is to aid clinicians in safely and effectively prescribing midazolam during the shortage of injectable lorazepam so that patients are provided the same effects and benefits.