Integrative Pharmacology in the Treatment of Substance Use Disorders.

The detrimental physical, mental, and socioeconomic effects of substance use disorders (SUDs) have been apparent to the medical community for decades. However, it has become increasingly urgent in recent years to develop novel pharmacotherapies to treat SUDs. Currently, practitioners typically rely on monotherapy. Monotherapy has been shown to be superior to no treatment at all for most substance classes. However, many randomized controlled trials (RCTs) have revealed that monotherapy leads to poorer outcomes when compared with combination treatment in all specialties of medicine. The results of RCTs suggest that monotherapy frequently fails since multiple dysregulated pathways, enzymes, neurotransmitters, and receptors are involved in the pathophysiology of SUDs. As such, research is urgently needed to determine how various neurobiological mechanisms can be targeted by novel combination treatments to create increasingly specific yet exceedingly comprehensive approaches to SUD treatment. This article aims to review the neurobiology that integrates many pathophysiologic mechanisms and discuss integrative pharmacology developments that may ultimately improve clinical outcomes for patients with SUDs. Many neurobiological mechanisms are known to be involved in SUDs including dopaminergic, nicotinic, N-methyl-D-aspartate (NMDA), and kynurenic acid (KYNA) mechanisms. Emerging evidence indicates that KYNA, a tryptophan metabolite, modulates all these major pathophysiologic mechanisms. Therefore, achieving KYNA homeostasis by harmonizing integrative pathophysiology and pharmacology could prove to be a better therapeutic approach for SUDs. We propose KYNA-NMDA-α7nAChRcentric pathophysiology, the "conductor of the orchestra," as a novel approach to treat many SUDs concurrently. KYNA-NMDA-α7nAChR pathophysiology may be the "command center" of neuropsychiatry. To date, extant RCTs have shown equivocal findings across comparison conditions, possibly because investigators targeted single pathophysiologic mechanisms, hit wrong targets in underlying pathophysiologic mechanisms, and tested inadequate monotherapy treatment. We provide examples of potential combination treatments that simultaneously target multiple pathophysiologic mechanisms in addition to KYNA. Kynurenine pathway metabolism demonstrates the greatest potential as a target for neuropsychiatric diseases. The investigational medications with the most evidence include memantine, galantamine, and N-acetylcysteine. Future RCTs are warranted with novel combination treatments for SUDs. Multicenter RCTs with integrative pharmacology offer a promising, potentially fruitful avenue to develop novel therapeutics for the treatment of SUDs.

Surge of Midazolam Use in the Midst of Lorazepam Shortage.

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.

COVID-19 and catatonia: Prevalence, challenges, pathophysiology, and treatment.

BACKGROUND: Emerging literature supports the association between acute COVID-19 infection and neuropsychiatric complications. This article reviews the evidence for catatonia as a potential neuropsychiatric sequela of COVID-19 infection. METHODS: PubMed was searched using the terms catatonia, severe acute respiratory syndrome coronavirus 2, and COVID-19. Articles were limited to those published in the English language between 2020 and 2022. Forty-five articles that specifically studied catatonia associated with acute COVID-19 infection were screened. RESULTS: Overall, 30% of patients with severe COVID-19 infection developed psychiatric symptoms. We found 41 cases of COVID-19 and catatonia, with clinical presentations that varied in onset, duration, and severity. One death was reported in a case of catatonia. Cases were reported in patients with and without a known psychiatric history. Lorazepam was successfully used, along with electroconvulsive therapy, antipsychotics, and other treatments. CONCLUSIONS: Greater recognition and treatment of catatonia in individuals with COVID-19 infection is warranted. Clinicians should be familiar with recognizing catatonia as a potential outcome of COVID-19 infection. Early detection and appropriate treatment are likely to lead to better outcomes.

Paper Charts: A Continued Barrier to Psychiatric Care in the Midst of a Broken and Fragmented Mental Health System.

ABSTRACT: The use of electronic medical records (EMRs) has increased dramatically over the last 15 years. However, psychiatry has lagged. EMRs are not being used by many mental health professionals. There are many reasons, including financial burden, lack of technological support, stigma, disaggregation of upfront costs, indirect benefits, and concerns about privacy and Health Insurance Portability and Accountability Act compliance. Obtaining paper records is a lengthy process, making continuity of care and emergency care challenging. Even when records are made available, it is common for information to be incomplete. The objective of this article is to highlight how the continued use of paper charts may decrease the quality and timeliness of psychiatric care provided and to discuss the psychiatry-specific issues created by EMRs. A case illustrating the disruption of care by continued use of paper charts in psychiatric facilities is presented. The growing use of EMR creates new challenges that affect psychiatry in ways other fields are not affected. These challenges include confidentiality issues, the frequent change/spectrum of diagnoses, determining how much information should be recorded in a note, and what the implications are of the information recorded. This article will discuss the use of EMRs in psychiatry, as well as encourage medical students and residents to take a deeper dive into psychiatry-specific issues regarding the use of EMR. EMR use may have a profound impact on our patient outcomes, health care delivery system, shorter inpatient stay, as well as reduce health care costs.

The Psychological Benefits of Cosmetic Surgery.

ABSTRACT: The objective of this review is to shed light on the literature regarding the psychological impact of invasive cosmetic surgery and to discuss future implications for research and clinical practice. Articles published through October 2021 were reviewed to answer the question, "Does cosmetic surgery improve a patient's overall psychological health?" Psychological well-being was examined through the lens of body image, self-esteem, anxiety, and depression scores. The studies revealed that although cosmetic surgery seems to boost patients' body image, other crucial aspects of psychological well-being may or may not similarly benefit. Notably, factors such as a patient's preoperative mental status, level of education, type of cosmetic procedure, postoperative healing time, sex, and age play a role in determining the direction and magnitude of psychological change after surgery. Limitations include the lack of diversity in study populations and the potential role of body dysmorphic disorder. Overall, researchers have concluded that cosmetic surgery improves body image but remain in disagreement on its effects on self-esteem, anxiety, and depression.

An Overview of Mindfulness-Oriented Addiction and Pain Recovery.

ABSTRACT: There is evidence that mindfulness-based interventions are effective as stress-reduction techniques in people with various stressor-related disorders. Research also shows overall improvement in mental health well-being in practitioners of mindfulness. However, there is limited literature probing the potential negative impacts of mindfulness practice. Relapse is a major challenge in substance use disorders (SUDs), particularly for people with chronic pain. There is an overlap between SUDs and chronic pain, which share common pathophysiological pathways that could contribute to poor pain control and mental instability. In this report, we discuss the possible effects of mindfulness on specified aspects of substance craving and chronic pain perception. We propose future directions for research in mindfulness practices to maximize the potential for relapse prevention and pain control.

Alpha7 nicotinic-N-methyl-D-aspartate hypothesis in the treatment of schizophrenia and beyond.

Development of novel treatments for positive, cognitive, and negative symptoms continue to be a high-priority area of schizophrenia research and a major unmet clinical need. Given that all randomized controlled trials (RCTs) conducted to date failed with one add-on medication/mechanism of action, future RCTs with the same approach are not warranted. Even if the field develops a medication for cognition, others are still needed to treat negative and positive symptoms. Therefore, fixing one domain does not completely solve the problem. Also, targeting the cholinergic system, glutamatergic system, and cholinergic plus alpha7 nicotinic and N-methyl-D-aspartate (NMDA) receptors failed independently. Hence, targeting other less important pathophysiological mechanisms/targets is unlikely to be successful. Meta-analyses of RCTs targeting major pathophysiological mechanisms have found some efficacy signal in schizophrenia; thus, combination treatments with different mechanisms of action may enhance the efficacy signal. The objective of this article is to highlight the importance of conducting RCTs with novel combination treatments in schizophrenia to develop antischizophrenia treatments. Positive RCTs with novel combination treatments that target the alpha7 nicotinic and NMDA receptors simultaneously may lead to a disease-modifying therapeutic armamentarium in schizophrenia. Novel combination treatments that concurrently improve the three domains of psychopathology and several prognostic and theranostic biomarkers may facilitate therapeutic discovery in schizophrenia.

Evidence for Using Doxazosin in the Treatment of Posttraumatic Stress Disorder.

There is evidence that doxazosin is effective in the treatment of posttraumatic stress disorder (PTSD). Doxazosin is a "me-too" drug of prazosin. Doxazosin has an improved absorption profile and this likely minimizes the risk for unintended adverse hypotensive effects. The availability of doxazosin in the gastrointestinal therapeutic system (GITS) form permits a higher initial daily dose (4 mg/day) while avoiding significant first-dose side effects. The treatment of PTSD with prazosin has several disadvantages due to its short duration of action (6-8 hours), which results in multiple doses being required. Prazosin may wear off and this may lead to nightmares in the latter half of the sleep. Doxazosin has significant advantages over prazosin in clinical practice because it has a long half-life and requires only once-daily dosing. This may lead to better adherence and greater effectiveness in the treatment of PTSD.

Adjunctive Minocycline in Clozapine-Treated Schizophrenia Patients With Persistent Symptoms.

OBJECTIVE: Clozapine is the most effective antipsychotic for treatment refractory people with schizophrenia, yet many patients only partially respond. Accumulating preclinical and clinical data suggest benefits with minocycline. We tested adjunct minocycline to clozapine in a 10-week, double-blind, placebo-controlled trial. Primary outcomes tested were positive, and cognitive symptoms, while avolition, anxiety/depression, and negative symptoms were secondary outcomes. METHODS: Schizophrenia and schizoaffective participants (n = 52) with persistent positive symptoms were randomized to receive adjunct minocycline (100 mg oral capsule twice daily; n = 29) or placebo (n = 23). RESULTS: Brief Psychiatric Rating Scale (BPRS) psychosis factor (P = 0.098; effect size [ES], 0.39) and BPRS total score (P = 0.075; ES, 0.55) were not significant. A change in total BPRS symptoms of more than or equal to 30% was observed in 7 (25%) of 28 among minocycline and 1 (4%) of 23 among placebo participants, respectively (P = 0.044). Global cognitive function (MATRICS Consensus Cognitive Battery) did not differ, although there was a significant variation in size of treatment effects among cognitive domains (P = 0.03), with significant improvement in working memory favoring minocycline (P = 0.023; ES, 0.41). The Scale for the Assessment of Negative Symptoms total score did not differ, but significant improvement in avolition with minocycline was noted (P = 0.012; ES, 0.34). Significant improvement in the BPRS anxiety/depression factor was observed with minocycline (P = 0.028; ES, 0.49). Minocycline was well tolerated with significantly fewer headaches and constipation compared with placebo. CONCLUSIONS: Minocycline's effect on the MATRICS Consensus Cognitive Battery composite score and positive symptoms were not statistically significant. Significant improvements with minocycline were seen in working memory, avolition, and anxiety/depressive symptoms in a chronic population with persistent symptoms. Larger studies are needed to validate these findings.

Prevalence of childhood physical and sexual abuse in veterans with psychiatric diagnoses.

We examined the prevalence of childhood (≤ 18 years) physical and sexual abuse reported among patients admitted to the psychiatric inpatient service and the differential rates of this abuse associated with psychiatric diagnoses. This study consisted of a retrospective chart review of 603 patients admitted to a psychiatric ward during a period of 1 year at Atlanta Veterans Affairs Medical Center who had data on childhood physical and sexual abuse. The prevalence of reported childhood physical or sexual abuse in this inpatient clinical population was 19.4% (117/603). The prevalence of reported physical abuse was 22.6% (19/84) in the women and 12.0% (62/519) in the men (p = 0.008); the prevalence of sexual abuse was 33.3% (28/84) in the women and 7.7% (40/519) in the men (p < 0.0001). More patients with depressive disorders reported sexual abuse than did those without these disorders. More patients with posttraumatic stress disorder (PTSD) reported physical and sexual abuse than did those without these disorders. Stratifying by race, sex, and diagnoses, multivariate analyses showed that the women with PTSD had a greater likelihood to report physical abuse (p = 0.03) and sexual abuse histories (p = 0.008) than did the women without PTSD. The men with substance-induced mood disorder (p = 0.01) were more likely to report physical abuse compared with the men without substance-induced mood disorder. Screening for abuse in patients with depressive disorders and PTSD is warranted to tailor individualized treatments for these patients. More research is needed to better understand the potential implications of childhood abuse on psychiatric diagnoses.

Association between adverse childhood experiences and suicidal behavior in schizophrenia spectrum disorders: A systematic review and meta-analysis.

Assessing and managing suicide behaviors is highly relevant to individuals with schizophrenia spectrum disorders. Our study aims to assess the association between adverse childhood experiences and suicidal behaviors in individuals with schizophrenia spectrum disorders. We included observational studies comparing the probability of suicide behaviors in adults with schizophrenia spectrum disorders exposed and unexposed to adverse childhood experiences. Odds ratio estimates were obtained by pooling data using a random-effects pairwise meta-analysis. Standardized criteria were used to assess the strength of the association of the pooled estimate. We found 21 eligible studies reporting outcomes for 6257 individuals from 11 countries. The primary outcome revealed an association between any suicidal behavior and adverse childhood experiences, which resulted "highly suggestive" according to validated Umbrella Criteria. Similarly, a positive association was confirmed for suicidal ideation and suicide attempt and for any subtype of adverse childhood experience. This meta-analysis showed that exposure to adverse childhood experiences strongly increases the probability of suicide behaviors in people with schizophrenia spectrum disorders.

The Potential Role of Long-acting Injectable Antipsychotics in People with Schizophrenia and Comorbid Substance Use.

OBJECTIVE: Treatment of schizophrenia in patients with comorbid substance use (alcohol/illicit drug use, abuse or dependence) presents challenges for public health systems. Substance use in people with schizophrenia is up to four times greater than the general population and is associated with medication nonadherence and poor outcomes. Therefore, continuous antipsychotic treatment in this population may pose more of a challenge than for those with schizophrenia alone. Many clinical trials and treatment recommendations in schizophrenia do not take into consideration substance use as people with comorbid substance use have typically been excluded from most antipsychotic trials. Nonetheless, antipsychotic treatment appears to be as efficacious in this population, although treatment discontinuation remains high. The objective of this review was to highlight the importance and utility of considering long-acting injectable antipsychotics for patients with schizophrenia and comorbid substance use. METHODS: We did a literature search using PubMed with key words schizophrenia and substance use/abuse/dependence, nonadherence, antipsychotics, long acting injectables, relapse, and psychosocial interventions. We limited our search to human studies published in English and 4,971 articles were identified. We focused on clinical trials, case reports, case series, reviews and meta-analyses resulting in 125 articles from 1975-2011. RESULTS: Our review suggests the potential role of long-acting injectables for people with comorbid substance use and schizophrenia in leading to improvements in psychopathology, relapse prevention, fewer rehospitalizations, and better outcomes. CONCLUSIONS: While more research is needed, long-acting antipsychotics should be considered an important option in the management of people with schizophrenia and comorbid substance use.

Case series on aripiprazole and dopamine supersensitivity psychosis.

A potential link between switching to aripiprazole and worsening of psychosis was first reported in the early 2000s. There have since been numerous published case reports describing this phenomenon, but only recently has the concept of a theoretical aripiprazole-induced dopamine supersensitivity psychosis (DSP) caused by D2 receptor activation in patients undergoing a switch to aripiprazole appeared in the literature. There is less awareness in clinical practice of the possibility of inducing DSP with aripiprazole, which may be particularly severe in some patients. The objective of this article is to present four cases demonstrating rapid and dramatic onset of DSP during switching to aripiprazole. In each case, a patient with a Diagnostic and statistical manual of mental disorders (5th ed.) diagnosis of schizophrenia experienced severe worsening of psychosis within 4-5 days of abrupt switching to aripiprazole from a full D2 antagonist. To our knowledge, this is the first case series characterizing the previously well-documented worsening of psychosis during switching to aripiprazole specifically as aripiprazole-induced DSP. We discuss clinical relevance, prevention and future directions. Careful cross-titration per clinical practice guidelines may reduce occurrence of DSP during aripiprazole switching or augmentation treatment.

Therapeutic Efficacy of Rhemercise: A Novel Mindfulness Technique in Patients With Opioid Use Disorder.

Objective: Rhemercise is a novel mindfulness technique used to prevent relapse in opioid use disorder (OUD). Rhemercise is a quantifiable and intentional slow-breathing technique that could increase subjective well-being, which helps to prevent relapse in OUD by reducing craving, negative affect, and visceral reactivity. The objective of this study was to assess the efficacy of rhemercise as an adjunctive therapy in patients with OUD undergoing detoxification.Methods: This was a hospital-based, open-label, prospective, and exploratory study conducted between June 2018 and June 2019 that included 126 male inpatients admitted for detoxification of OUD. Patients with OUD diagnosed according to ICD-10 criteria who were aged 18-65 years were included in the study. Patients with other psychiatric disorders were excluded. Participants were divided into 2 groups: group A (n = 63) comprised patients receiving treatment as usual + rhemercise, and group B (n = 63) received treatment as usual only. Assessment tools included the Clinical Opiate Withdrawal Scale, Brief Pain Inventory, and Subjective Well-Being Inventory.Results: Various domains of the Subjective Well-Being Inventory (general well-being-positive affect [P = .02], confidence in coping [P = .007], inadequate mental mastery [P = .002]) improved significantly among OUD patients who received rhemercise treatment compared to treatment as usual.Conclusion: Rhemercise promoted general well-being and positive affect and decreased the opioid withdrawal symptoms, thereby potentially reducing the overall risk for relapse. Future studies are warranted with rhemercise to validate these promising findings.

Case report on the management of depression in schizoaffective disorder, bipolar type focusing on lithium levels and measurement-based care.

There is little evidence supporting the management of depression in schizoaffective disorder, bipolar type. Managing bipolar depression can be a daunting task for clinicians. Most bipolar patients spend 80% of their time in the depressive phase of illness. In contrast with full-blown mania, patients and family frequently fail to recognize bipolar depression, which may interfere with early diagnosis and treatment. With only a few medications approved for bipolar depression, treatment becomes very challenging. There is evidence to support that schizoaffective depression has a worse outcome than psychotic depression and nonpsychotic depression. We report a patient with schizoaffective disorder, bipolar type with severe depression who responded to an adequate level of lithium and subsequently, on a combination of lithium and quetiapine. Finally, we emphasize the importance of measurement-based care. To our knowledge, this is the first case report focusing on the management of depression in schizoaffective disorder, bipolar type.

Galantamine-Memantine Combination and Kynurenine Pathway Enzyme Inhibitors in the Treatment of Neuropsychiatric Disorders.

The kynurenine pathway (KP) is a major route for L-tryptophan (L-TRP) metabolism, yielding a variety of bioactive compounds including kynurenic acid (KYNA), 3-hydroxykynurenine (3-HK), quinolinic acid (QUIN), and picolinic acid (PIC). These tryptophan catabolites are involved in the pathogenesis of many neuropsychiatric disorders, particularly when the KP becomes dysregulated. Accordingly, the enzymes that regulate the KP such as indoleamine 2,3-dioxygenase (IDO)/tryptophan 2,3-dioxygenase, kynurenine aminotransferases (KATs), and kynurenine 3-monooxygenase (KMO) represent potential drug targets as enzymatic inhibition can favorably rebalance KP metabolite concentrations. In addition, the galantamine-memantine combination, through its modulatory effects at the alpha7 nicotinic acetylcholine receptors and N-methyl-D-aspartate receptors, may counteract the effects of KYNA. The aim of this review is to highlight the effectiveness of IDO-1, KAT II, and KMO inhibitors, as well as the galantamine-memantine combination in the modulation of different KP metabolites. KAT II inhibitors are capable of decreasing the KYNA levels in the rat brain by a maximum of 80%. KMO inhibitors effectively reduce the central nervous system (CNS) levels of 3-HK, while markedly boosting the brain concentration of KYNA. Emerging data suggest that the galantamine-memantine combination also lowers L-TRP, kynurenine, KYNA, and PIC levels in humans. Presently, there are only 2 pathophysiological mechanisms (cholinergic and glutamatergic) that are FDA approved for the treatment of cognitive dysfunction for which purpose the galantamine-memantine combination has been designed for clinical use against Alzheimer's disease. The alpha7 nicotinic-NMDA hypothesis targeted by the galantamine-memantine combination has been implicated in the pathophysiology of various CNS diseases. Similarly, KYNA is well capable of modulating the neuropathophysiology of these disorders. This is known as the KYNA-centric hypothesis, which may be implicated in the management of certain neuropsychiatric conditions. In line with this hypothesis, KYNA may be considered as the "conductor of the orchestra" for the major pathophysiological mechanisms underlying CNS disorders. Therefore, there is great opportunity to further explore and compare the biological effects of these therapeutic modalities in animal models with a special focus on their effects on KP metabolites in the CNS and with the ultimate goal of progressing to clinical trials for many neuropsychiatric diseases.

Galantamine-Memantine combination in the treatment of Alzheimer's disease and beyond.

Alzheimer's disease (AD) is the most prevalent form of dementia in the elderly population worldwide. Despite the major unmet clinical need, no new medications for the treatment of AD have been approved since 2003. Galantamine is an acetylcholinesterase inhibitor that is also a positive allosteric modulator at the α4ß2 and α7nACh receptors. Memantine is an N-methyl-d-aspartate receptor modulator/agonist. Both galantamine and memantine are FDA-approved medications for the treatment of AD. The objective of this review is to highlight the potential of the galantamine-memantine combination to conduct randomized controlled trials (RCTs) in AD. Several studies have shown the combination to be effective. Neurodegenerative diseases involve multiple pathologies; therefore, combination treatment appears to be a rational approach. Although underutilized, the galantamine-memantine combination is the standard of care in the treatment of AD. Positive RCTs with the combination with concurrent improvement in symptoms and biomarkers may lead to FDA approval, which may lead to greater utilization of this combination in clinical practice.