Dawn Bruijnzeel

Lurasidone in the treatment of schizophrenia: a critical evaluation

Introduction: Antipsychotic medications are the foundation of the pharmacological treatment of schizophrenia and lurasidone is the most recent of the 65 agents around the world to become available. In order to use it optimally, it is important to understand its pharmacological and clinical nature and its comparative effectiveness to other antipsychotic agents in the treatment of schizophrenia. Areas covered: Following a comprehensive review of the literature, this article summarizes current information about the pharmacology of lurasidone, data about its short- and long-term efficacy and safety/tolerability in the treatment of schizophrenia, its comparative effectiveness to other antipsychotic agents, and guidance about its optimal use in the treatment of individuals with schizophrenia. Expert opinion: Lurasidone is a benzoisothiazole with potent dopamine D2 and serotonin 5HT2A antagonist and serotonin 5HT1A partial agonist properties (like other second-generation antipsychotic agents) with additional potent 5HT7 and alpha2C noradrenergic antagonism. It has little or no activity at the alpha1 and alpha2A noradrenergic, 5HT2C serotonergic, histaminergic and cholinergic receptors. Available only in an oral formulation, it is effective in once-daily dosing (40 – 160 mg/day) and its absorption is affected by food. There is an extensive clinical trial database with short-term and long-term placebo- and antipsychotic-controlled clinical trials evaluating the efficacy and safety/tolerability of lurasidone in the treatment of schizophrenia. It has been found to be efficacious with comparable efficacy to other agents in the treatment of acute psychosis and prevention of relapse in individuals with schizophrenia. The greater antidepressant and cognitive benefits suggested by its receptor profile need substantiation in robust clinical trials. It is less likely to cause metabolic and cardiac adverse effects than most other second-generation agents and is associated with a modest risk of extrapyramidal side-effects, akathisia, and prolactin elevation.

Spotlight on brexpiprazole and its potential in the treatment of schizophrenia and as adjunctive therapy for the treatment of major depression

Antipsychotic agents, utilized for the treatment of a range of psychiatric disorders, differ substantially in terms of their pharmacology and adverse effect profiles. Incomplete and variable efficacy, differences in safety–tolerability, and highly heterogeneous response across individuals prompt development of new agents. Brexpiprazole is one of the two most recently introduced antipsychotic agents approved for the treatment of schizophrenia and as an adjunct for treatment of major depressive disorder. Its pharmacology, clinical trial data, and efficacy and side effects in comparison with other antipsychotic agents are discussed. Brexpiprazole is a dopamine D-2 partial agonist with potent activity at the serotonin 5HT1A and 5HT2A and noradrenergic alpha-1B and alpha-2C receptors. Placebo-controlled clinical trials in persons with schizophrenia support its efficacy in treating psychosis and preventing relapse. Short-term clinical trials also support its efficacy as an adjunct to antidepressants in treating major depressive disorder in individuals inadequately responsive to antidepressant treatment alone. Adverse effects include akathisia, gastrointestinal side effects, and moderate weight gain. The recommended oral dose of brexpiprazole is 2–4 mg/day in schizophrenia and 2–3 mg/day as adjunctive treatment in major depression. It must be titrated up to its target dose over 1–2 weeks and is effective in once-daily dosing. How brexpiprazole’s unique pharmacological profile will translate into clinically meaningful differences from other antipsychotic agents is unclear. Its place in our antipsychotic armamentarium and potential role in the treatment of schizophrenia and major depressive disorder will be determined by additional clinical data and experience.

Pros and cons of medical cannabis use by people with chronic brain disorders.

Background: Cannabis is the most widely used illicit drug in the world and there is growing concern about the mental health effects of cannabis use. These concerns are at least partly due to the strong increase in recreational and medical cannabis use and the rise in tetrahydrocannabinol (THC) levels. Cannabis is widely used to self-medicate by older people and people with brain disorders such as amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), Alzheimer’s disease (AD), Parkinson’s disease (PD), bipolar disorder, and schizophrenia. Objective: This review provides an overview of the perceived benefits and adverse mental health effects of cannabis use in people with ALS, MS, AD, PD, bipolar disorder, and schizophrenia. Results: The reviewed studies indicate that cannabis use diminishes some symptoms associated with these disorders. Cannabis use decreases pain and spasticity in people with MS, decreases tremor, rigidity, and pain in people with PD, and improves the quality of life of ALS patients by improving appetite, and decreasing pain and spasticity. Cannabis use is more common among people with schizophrenia than healthy controls. Cannabis use is a risk factor for schizophrenia which increases positive symptoms in schizophrenia patients and diminishes negative symptoms. Cannabis use worsens bipolar disorder and there is no evidence that bipolar patients derive any benefit from cannabis. In late stage Alzheimer’s patients, cannabis products may improve food intake, sleep quality, and diminish agitation. Conclusion: Cannabis use diminishes some of the adverse effects of neurological and psychiatric disorders. However, chronic cannabis use may lead to cognitive impairments and dependence.

Antipsychotic Polypharmacy: State of the Science and Guidelines for Practice. It’s difficult to stop once you start

espite a scanty evidence base, the concurrent use of two or more antipsychotic medications has become increasingly prevalent. The limited data on this practice provide no support for its effectiveness, except for the potential utility of adding a second antipsychotic agent to clozapine in patients with otherwise treatment-refractory schizophrenia. A number of adverse associations of antipsychotic combinations have been reported, including higher mortality, an increased risk of a range of side-effects, adverse drug interactions, decreased treatment adherence, and greater costs. We evaluate the appropriateness of the many rationales for antipsychotic combinations and outline recommendations for its place in antipsychotic therapy.

Antipsychotic treatment of schizophrenia. We can do better

While existing treatments are neither fully efficacious nor devoid of significant adverse effects, the effectiveness of antipsychotic treatment for schizophrenia has been well demonstrated (Tandon, 2011; Tiihonen et al., 2011 and 2016). Since the introduction of chlorpromazine into clinical practice sixty years ago, there have been continuing advances in antipsychotic drug development. Currently, 67 different agents with a broad range of clinical attributes and formulations are available around the world (Bruijnzeel et al., 2014). Despite vigorous efforts, however, schizophrenia continues to be associated with high morbidity and mortality. The mortality gap for persons with schizophrenia has, in fact, been increasing over the past several decades. What accounts for this discrepancy? Are we using available treatments for schizophrenia optimally? Are we appropriately utilizing the array of available antipsychotic treatment options and matching them to individual patient needs and response? Can we do better (Catts and O’Toole, 2016)? As observed by Sreeraj and co-workers in this issue of the Journal (2017a and b), the two most underutilized antipsychotic treatment options in schizophrenia (namely clozapine and long-acting injectable agents) are infrequently prescribed by clinicians because of a gap between research evidence and clinical practice. Clinicians are not fully cognizant of the benefits of clozapine and long-acting antipsychotics and overestimate the potential risks and side-effects of these agents. As Sreeraj and co-workers (2017a) note, the use of clozapine is generally not considered in schizophrenia patients with co-morbid diabetes mellitus because of an exaggerated perception of differential risk and inadequate knowledge of approaches to mitigate that risk (Tandon and Halbreich, 2003). They present a case series of persons with schizophrenia and co-morbid diabetes mellitus who were safely and effectively treated with clozapine. Studies of prescriber attitudes towards clozapine (Grover et al., 2015) have confirmed magnified perceptions of risk leading to its significant underutilization. Since it is the only agent shown to be significantly more effective than other antipsychotics in the treatment of refractory schizophrenia, ensuring appropriate use of clozapine is a public health imperative. In a similar manner, clinicians appear to be inadequately aware of the benefits of long-acting injectable antipsychotics (LAIs) and magnify risks/ challenges associated with their use (Gundugarti et al., 2017; Heres et al., 2014; Suzuki et al., 2017). Sreeraj and co-workers (2017b) note that just as clinicians have an incomplete understanding of the research evidence about LAIs, researchers are not addressing many clinically relevant questions about the use of these agents in persons with schizophrenia. To achieve optimal therapy for schizophrenia, clinicians must balance efficacy, risks and benefits of treatments in a way that is customized for the needs and vulnerabilities of the individual patient. As decisions about antipsychotic therapy often entail a trial and error process involving careful monitoring of response and adverse effects, an ongoing risk-benefit assessment is essential. Optimal antipsychotic treatment to promote recovery in each individual with schizophrenia requires definition of treatment goals and targets, use of a proper antipsychotic trial algorithm, measurementbased care, and collaborative decision-making (Tandon et al., 2006). Both clozapine and long-acting injectable antipsychotics have an important role in the treatment of schizophrenia as below: Proper antipsychotic trial algorithm

Modelling schizophrenia: Opportunities and challenges

Schizophrenia is a complex neuropsychiatric disorder caused by interactions between multiple genetic and environmental factors, with specific risk genes and environmental risk factors being identified. Despite incredible advances in molecular neuroscience andgenetics accompaniedbythedevelopmentofarangeofpowerful imaging and other technologies to investigate the brain, however, our understanding of the pathophysiology of schizophrenia remains before the horse” in our application of various technologies to the study of schizophrenia. We get so enamored by the potency of a new investigative technique that we apply it in an indiscriminate manner and are stuck with “another set of hundreds of new findings” that are uninformative; instead of building a coherent structure of knowledge about schizophrenia, they lie around like bricks in a brickyard (Platt, 1964).

The Evolving Nosology of Schizophrenia: Relevance for Treatment

The purpose of nosological systems (i.e., systems of classifying disease) is to define distinct disease entities which are uniquely identifiable and specifically treatable. Consequently, validity, reliability, and clinical utility are three critical elements of a useful diagnostic system. Our system of psychiatric classification recently underwent a major revision, resulting in the publication of the Diagnostic and Statistical Manual of Mental Disorders (DSM)-5 in 2013. Whereas improving validity and reliability of psychiatric diagnoses were key objectives in its development, enhancing clinical utility was the primary goal. With reference to psychotic disorders, changes in the new manual addressed limitations in DSM-IV while incorporating new information about the nature of these disorders generated over the past 20 years. With regard to schizophrenia, variation in distinct psychopathological dimensions is better able to account for the heterogeneity of this disorder than traditional subtypes. Therefore, changes in DSM-5 included elimination of the classic subtypes of schizophrenia and the addition of unique psychopathological dimensions. In view of the poor reliability and limited validity of schizoaffective disorder as defined in DSM-IV a clearer definition was provided in DSM-5. Additionally, the discrepant treatment of catatonia in DSM-IV has been corrected and it is now listed consistently across the DSM-5 manual. A new category of Attenuated Psychosis Syndrome is included in Section 3 as a condition for further study. In this chapter, the revisions in the DSM-5 criteria for schizophrenia spectrum and other psychotic disorders are summarized and their implications for clinical practice discussed.