Advances in the Treatment of Chronic Insomnia: A Narrative Review of New Nonpharmacologic and Pharmacologic Therapies.

Chronic insomnia disorder, which affects 6-10% of the population, is diagnostically characterized by ongoing difficulties with initiating or maintaining sleep occurring at least three times per week, persisting for at least 3 months, and associated with daytime impairment. While chronic insomnia is often considered a condition primarily related to impaired sleep, the disorder can also adversely affect domains of physical and mental health, quality of life, and daytime function, which highlights the importance of treating the multidimensional sleep disorder. Owing to misperceptions about the safety and effectiveness of treatment options, many individuals with insomnia may not seek professional treatment, and alternatively use ineffective home remedies or over-the-counter medications to improve sleep. Some physicians may even believe that insomnia is remediated by simply having the patient "get more sleep". Unfortunately, treatment of insomnia is not always that simple. The disorder's complex underlying pathophysiology warrants consideration of different nonpharmacologic and pharmacologic treatment options. Indeed, recent insights gained from research into the pathophysiology of insomnia have facilitated development of newer treatment approaches with more efficacious outcomes. This narrative review provides a summary of the diagnostic criteria and pathophysiology of insomnia and its subtypes. Further, this review emphasizes new and emerging nonpharmacologic and pharmacologic treatments for chronic insomnia, including recent enhancements in approaches to cognitive behavioral therapy for insomnia (CBT-I) and the new dual orexin receptor antagonist (DORA) pharmacologics. These advances in treatment have expanded the treatment options and are likely to result in improved outcomes in patients with chronic insomnia.

Agitation in schizophrenia: origins and evidence-based treatment.

PURPOSE OF REVIEW: Agitation associated with schizophrenia remains an important clinical concern and if not managed effectively, can escalate into aggressive behavior. This is a review of the recent biomedical literature on agitation in individuals with schizophrenia. RECENT FINDINGS: Themes in the recent literature include consideration of comorbidities such as cigarette smoking and cannabis use. Surveys reveal that pharmacological approaches to manage agitation have changed little, with haloperidol remaining in common use and intramuscular administration of antipsychotics and/or benzodiazepines being frequently administered to more severely agitated/aggressive individuals. Of note, ketamine has been recently adopted for use in severe agitation in medical emergency departments, but the risk of this medication for people with schizophrenia is unclear. At present, inhaled loxapine remains the only rapidly acting noninjectable FDA-approved treatment for agitation associated with schizophrenia. In development is an intranasal formulation for olanzapine (a well characterized atypical antipsychotic already approved to treat agitation) and a sublingual film for dexmedetomidine (an α2-adrenergic agonist used as an anesthetic and now being repurposed). SUMMARY: Comorbidities can contribute to agitation and can make an accurate differential diagnosis challenging. The ongoing development of rapidly acting novel formulations of antiagitation medications, if successful, may facilitate clinical treatment by providing additional options.

The preclinical profile of brexpiprazole: what is its clinical relevance for the treatment of psychiatric disorders?

Brexpiprazole is a serotonin-dopamine activity modulator in clinical development for schizophrenia, adjunctive treatment of major depressive disorder, agitation in Alzheimer's disease and post-traumatic stress disorder. It is a partial agonist at 5-HT1A and D2 receptors with similar potency, and an antagonist at 5-HT2A and adrenergic α1B/2C receptors. Compared with aripiprazole, brexpiprazole is more potent at 5-HT1A receptors and displays less intrinsic activity at D2 receptors. This unique serotonin and dopamine modulatory activity has shown robust antipsychotic, antidepressant-like and anxiolytic activities, and limited extrapyramidal symptom liability with pro-cognitive efficacy in animal models. Phase III clinical trials have been successfully completed in schizophrenia and adjunctive use in major depressive disorder, with the US FDA approval obtained for these uses; Phase III studies in Alzheimer's disease and post-traumatic stress disorder are ongoing.

Oral paliperidone extended-release: chemistry, pharmacodynamics, pharmacokinetics and metabolism, clinical efficacy, safety and tolerability.

INTRODUCTION: Paliperidone is a second-generation (atypical) antipsychotic approved for the treatment of schizophrenia in adults and in adolescents aged 12 - 17 years. It is also approved for the treatment of adults with schizoaffective disorder, both as a monotherapy and as adjunctive therapy to mood stabilizers and/or antidepressants. Paliperidone is the active metabolite of risperidone. AREAS COVERED: The purpose of this review is to describe the pharmacokinetic profile of paliperidone and its clinical implications in the treatment of schizophrenia and schizoaffective disorder. Background information is also provided regarding chemistry, pharmacodynamics, clinical efficacy and safety/tolerability data. EXPERT OPINION: The recommended dose of paliperidone extended-release (ER) in adults is 6 mg/day and no initial dose titration is required. Higher doses may provide additional benefit as well as dose-related increases in some adverse reactions. The maximum recommended dose is 12 mg/day. Peak plasma concentrations are reached approximately 24 h after dosing. Pharmacokinetics are dose-proportional. Terminal half-life is approximately 23 h. Renal excretion is the major route of elimination. Although paliperidone is the active metabolite of risperidone, paliperidone's route of metabolism and elimination is quite different from that for risperidone and paliperidone ER may be preferred over risperidone when liver disease, drug-drug interactions or other alterations in metabolism render the appropriate dosing of risperidone difficult to determine for an individual patient. The use of paliperidone ER will need to be considered within the context of its cost and availability as risperidone is now a generic product.

Spirituality, schizophrenia, and state hospitals: program description and characteristics of self-selected attendees of a spirituality therapeutic group.

Spiritual matters can be an important part in the recovery process of patients with schizophrenia. A spirituality-based therapeutic group was developed for patients hospitalized on a research specialty unit jointly operated by a state hospital and a research institute. This report offers a description of this program and examines potential associations between spirituality and coping in patients with schizophrenia who either attended or did not attend the inpatient spirituality group. We compared group attendees (n = 20) with non-attendees (n = 20) cross-sectionally, using measures of spirituality, self-efficacy (i.e. the confidence in one's ability), quality of life, and hopefulness, and religious/personal demographic profiles. For the total sample, spirituality status was significantly correlated with self-efficacy for both social functioning and negative symptoms. Significant differences were found between group attendees and non-attendees for spirituality status, but not for self-efficacy or quality of life. For group attendees, spirituality status was significantly correlated with self-efficacy for positive symptoms, negative symptoms and social functioning. Group attendees were significantly more hopeful than non-attendees and hopefulness was significantly associated with degree of spirituality status. These findings lend support for offering spirituality groups and positive coping during recovery from psychiatric disabilities.

Public-academic partnerships: integrating state psychiatric hospital treatment and clinical research.

Collaboration between state clinical treatment services and academic research is fertile ground for clinical research opportunities. Such joint initiatives require careful planning, including provisions for joint training, integration of research staff into clinical activities, and integration of clinical treatment staff into research activities. The authors describe the planning and development of a 24-bed research unit at the Nathan S. Kline Institute for Psychiatric Research, colocated on the same campus as Rockland Psychiatric Center, each of which is an independent facility operated by the New York State Office of Mental Health.

Antipsychotics and hyperprolactinaemia: clinical recommendations.

A group of international experts in psychiatry, medicine, toxicology and pharmacy assembled to undertake a critical examination of the currently available clinical guidance on hyperprolactinaemia. This paper summarises the group's collective views and provides a summary of the recommendations agreed by the consensus group to assist clinicians in the recognition, clinical assessment, investigation and management of elevated plasma prolactin levels in patients being treated for severe mental illness. It also deals with the special problems of particular populations, gives advice about information that should be provided to patients, and suggests a strategy for routine monitoring of prolactin. The recommendations are based upon the evidence contained in the supplement 'Hyperprolactinaemia in schizophrenia and bipolar disorder: Clinical Implications' (2008). The guidance contained in this article is not intended to replace national guidance (such as that of the National Institute of Clinical Excellence), however, it does provide additional detail that is unlikely to be covered in existing guidelines, and focuses on areas of uncertainty and disagreement. We hope it will add to the debate about this topic.

Are we treating schizophrenia effectively? Understanding the primary outcomes of the CATIE study.

The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study for schizophrenia was designed to independently evaluate the effectiveness of antipsychotic treatment in "real-world" patients. To assess the effectiveness of the conventional antipsychotics compared to the atypicals as well as the differences among the atypicals, patients were randomized to one of four atypical antipsychotics (olanzapine, quetiapine, risperidone, ziprasidone) or a representative conventional antipsychotic (perphenazine). Effectiveness was defined by time to discontinuation and duration of successful treatment. Time to "all-cause" discontinuation reflects both efficacy (ability of a drug to reduce symptoms) and safety/tolerability. Phase I revealed discontinuation rates ranging from 64% for olanzapine to 82% for quetiapine. Differences among the medications may be important in the selection of a drug for a particular patient. Physicians should involve the patient in choosing their medication by inquiring about the patient's past experience with medications and side effects, educating the patient on the risk-benefit ratio, and considering the patient's preference. To demonstrate how results of the CATIE study can contribute to the knowledge of practicing clinicians, this monograph presents a representative clinical case patient and illustrates how the CATIE safety and efficacy data has important implications for the patient.

Diabetes and schizophrenia 2005: are we any closer to understanding the link?

The association between schizophrenia and diabetes has been recognized for well over a century, but the underlying reasons for this association are unclear. In October 2003, an international group of diabetologists and psychiatrists met to review the literature relating to the association, and to create pragmatic guidelines for the management of diabetic risk in patients with severe mental illness. Since that meeting, over 100 additional papers have been published on the association between glucose abnormalities and schizophrenia, and this is a clear reflection of the level of interest in this clinically important area. Diabetes is highly prevalent among the schizophrenia population, but most sufferers remain undiagnosed in the community. The reasons why individuals with schizophrenia are more prone to developing diabetes than the general population are poorly defined, but likely to be multifactorial. The role of antipsychotic medications in the development of diabetes and other pre-diabetic states remains controversial, but it appears that the attributable risk is low. Traditional risk factors most probably account for much of the diabetes seen in schizophrenia populations, suggesting that routine screening and aggressive risk factor management are especially important in this patient group.

Metabolic syndrome and cardiovascular disease.

Metabolic syndrome is a constellation of clinical findings that identify individuals at higher than normal risk of developing diabetes mellitus or cardiovascular disease. There are two principal definitions, one emerging from the American National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults, and the other from the World Health Organization. Both definitions share the common elements of abdominal obesity, hypertriglyceridaemia, low HDL-cholesterol, hypertension and abnormal glucose regulation. The syndrome is relatively common across continents, and also among those without marked obesity. It is even more common among patients with major mental health disorders such as schizophrenia. Metabolic syndrome can be used to assess risk for cardiovascular disorder and death, and is an alternative to Framingham Risk Calculations. C-reactive protein may play an additional role in risk prediction. Ongoing monitoring for all components of the metabolic syndrome is necessary. Individuals at high risk require multimodal interventions, including lifestyle interventions and targeted medications as appropriate.

Do guidelines for severe mental illness promote physical health and well-being?

The effective management of individuals with severe mental illnesses (SMIs) requires an holistic approach that offers reliable symptom control, but also addresses other clinical, emotional and social needs. The physical health of individuals with an SMI is often poor, with many being overweight or obese, having hypertension, diabetes or dyslipidaemia, and at significant risk of developing cardiovascular disease or other comorbidities. We have recently reviewed current UK and US guidelines for the management of individuals with schizophrenia and bipolar disorder, and found very different approaches to the holistic care of people with SMIs, especially in relation to the management of physical health and cardiovascular risk. UK guidelines acknowledge the high risk of physical morbidity and mortality in individuals with an SMI, but fail to address in detail the specifics of physical health monitoring and lifestyle management. US guidelines are more descriptive in terms of the type and extent of monitoring recommended, but there are inconsistencies between the guidelines produced by different organizations, and studies in the field suggest that none of them is being adequately implemented. Clear and consistent recommendations on how and when to monitor weight, cardiovascular function, and metabolic parameters and, importantly, what to do with the results, would support clinicians wishing to integrate physical and mental healthcare. Publication of specific recommendations on evidence-based physical health interventions that can work for people with SMIs would also help primary care and mental health services improve general well-being in their patients with severe mental illnesses.

Efficacy of the branched-chain amino acids in the treatment of tardive dyskinesia in men.

OBJECTIVE: The efficacy of the branched-chain amino acids in the treatment of tardive dyskinesia in men with psychiatric disorders was tested. METHOD: Public-sector psychiatric patients with long histories of antipsychotic treatment and presumably long-standing tardive dyskinesia were randomly assigned to receive branched-chain amino acids or placebo. Treatment frequency was three times a day, 7 days a week for 3 weeks. The efficacy measure was a frequency count of videotaped tardive dyskinesia movements. RESULTS: A robust and highly significant difference was observed between patients who received high-dose branched-chain amino acids (222 mg/kg of body weight t.i.d.) (N=18) and those who received placebo (N=18) in the percent change in tardive dyskinesia symptoms from baseline to the end of the 3-week trial. Significant and marked differences were seen between the two groups at the >/=30% and >/=60% levels of decrease in tardive dyskinesia symptoms. No clinically significant differences were seen between the pre- and posttrial results of physical examinations and laboratory screening tests. Minimal gastrointestinal symptoms occurred during the trial. The reduction in tardive dyskinesia symptoms in the amino acids group was not related to changes in antipsychotic and glucose plasma levels. A mechanism of response related to decreased amine neurotransmitter synthesis was suggested by the significant positive correlations observed between decreases in tardive dyskinesia symptoms and decreases in aromatic amino acid plasma concentrations over the course of the trial. CONCLUSIONS: Branched-chain amino acids constitute a novel, safe treatment for tardive dyskinesia, with a strong potential for providing significant improvement in the diseased physiognomy of the afflicted person.