Jeffrey Rado

Pharmacological and clinical profile of recently approved second-generation antipsychotics: implications for treatment of schizophrenia in older patients.

Antipsychotics are frequently used in elderly patients to treat a variety of conditions, including schizophrenia. While extensively studied for their impact in younger populations, there is comparatively limited evidence about the effectiveness of these agents in older patients. Further complicating this situation are the high comorbidity rates (both psychiatric and medical) in the elderly; age-related changes in pharmacokinetics that lead to a heightened proclivity for adverse effects; and the potential for multiple, clinically relevant drug interactions. With this background in mind, we review diagnostic and treatment-related issues specific to elderly patients suffering from schizophrenia. We then focus on the potential role of the most recently approved second-generation antipsychotics, paliperidone (both the extended-release oral formulation and the long-acting injectable formulation), iloperidone, asenapine and lurasidone, given the limited clinical experience with these agents in the elderly. While there is limited data to support their safety, tolerability and efficacy in older patients with schizophrenia, each has unique characteristics that should be considered when used in this population.

Integrated Medicine and Psychiatry Curriculum for Psychiatry Residency Training: A Model Designed to Meet Growing Mental Health Workforce Needs

Patients with chronic mental illness have significantly higher rates of medical comorbidity and resultant lower life expectancies when compared to the general population [1–3]. This survival discrepancy is not fully accounted for by the higher rate of suicide completion in these patients but, rather, is often attributable to mortality from cardiovascular, metabolic, and other systemic illness. Many such individuals are seen in community mental health settings and have poor access to primary health care. In some cases, the psychiatrist may become the “de facto primary care physician,”while providing some preventive health screening and treatment of general medical conditions. For those patients who are cared for by a primary care provider, the psychiatrist may support preventive medical recommendations with psychopharmacological interventions and the use of psychotherapies such as cognitive behavioral therapy, problem solving therapy, supportive psychotherapy, and motivational interviewing. Strong evidence calls for improved general medical care for people with severe mental illnesses. In a 17-year followup study of over 80,000 people in the USA, those with mental illness died an average of 8.2 years earlier than those without mental illness, with excess mortality primarily due to socioeconomic factors, poor access to effective primary and preventative care, and the burden of chronic health conditions [1]. Moreover, individuals with schizophrenia tend to die 20– 30 years earlier than the population average, even after excluding deaths by suicide [2]. Similarly, those with bipolar disorder have a twofold higher mortality rate than the general population [3]. Patients with major depression are also at higher risk of medical illness, such as diabetes mellitus and ischemic heart disease [4, 5]. The increased risk of diabetes mellitus, metabolic syndrome, cardiovascular disease, and stroke associated with atypical antipsychotics further underscores the need for the psychiatrist to engage in risk factor monitoring, risk reduction, and recognition and management of comorbid medical conditions in their patients [6–8]. Given the significantly increased mortality among psychiatric patients as a result of non-psychiatric medical conditions, it is essential we provide psychiatric training that mirrors significant changes to our mental health delivery system by way of the Patient Protection and Affordable Care Act. Psychiatry residents should receive training about collaborative and targeted preventive medical care, which better approximates current and real-world clinical practice guidelines found in patient-centered medical homes. We suggest one approach to accomplishing this is to provide residents with an Integrated Medicine and Psychiatry (IMAP) curriculum.

Quetiapine for the treatment of acute bipolar mania, mixed episodes and maintenance therapy

Introduction: Bipolar disorder is characterized by mood instability, which can be challenging to manage. First-line pharmacological approaches usually involve lithium, anticonvulsants and antipsychotics. Over the past fifteen years, several second-generation antipsychotics have demonstrated benefits for various phases of this disorder. Areas covered: This article examines the pharmacodynamics and pharmacokinetics of quetiapine; its evidence base as an acute and maintenance monotherapy or adjunctive therapy for bipolar manic or mixed episodes is also discussed, along with the related issues of its safety and tolerability. Expert opinion: In the context of bipolar disorder, quetiapine is the only agent approved as a monotherapy or adjunct therapy for acute manic/mixed episodes in adults and adolescents; as a monotherapy for acute depressive episodes in adults; and as an adjunctive maintenance therapy for bipolar I and II disorder in adults. In addition to its antipsychotic properties, this broad mood-stabilizing potential may simplify the management of select patients.

Iloperidone for schizophrenia

Importance of the field: No existing antipsychotic adequately controls all symptoms associated with schizophrenia. Also, no antipsychotic adequately benefits most patients with this disorder. Finally, the safety and tolerability of each antipsychotic frequently dictate the choice of agent. Areas covered in the review: The mechanism of action of iloperidone, its efficacy and its safety and tolerability when used to treat patients with schizophrenia. What the reader will gain: An appreciation of the potential advantages and disadvantages of iloperidone when used for the treatment of schizophrenia. Take home message: Iloperidone is a recent addition to the current group of second-generation antipsychotics. While it may share many qualities with other agents in this class, its unique neuroreceptor signature and adverse-effect profile may prove beneficial in clinical practice.

Long-term efficacy and safety of iloperidone: an update

Schizophrenia is a devastating neuropsychiatric disease with a worldwide prevalence of approximately 0.5%–1%. Since many patients do not achieve adequate symptom relief from available agents, alternate pharmacotherapeutic approaches are needed. In this context, iloperidone was recently approved by the US Food and Drug Administration for the treatment of schizophrenia. This paper first reviews its pharmacodynamic and pharmacokinetic profiles, emphasizing their clinical relevance. Next, it summarizes the literature on its acute and maintenance efficacy, safety, and tolerability. It then considers pharmacogenetic data which may help to predict response and risk of cardiac arrhythmias with this agent. Finally, it critically positions iloperidone relative to other first- and second-generation antipsychotics.

Quetiapine monotherapy for bipolar depression

Introduction: Depression, in the context of bipolar disorder, is more prevalent than hypomania or mania and accounts for most of the disability. Furthermore, the treatment of bipolar depression is more complicated than the treatment of unipolar major depression. Finally, the evidence base for pharmacotherapy of bipolar depression is much smaller than for unipolar depression or hypomania/mania. Areas covered: The article examines the mechanism of action and pharmacokinetics of quetiapine, its evidence base as a treatment for bipolar depression and related issues of safety and tolerability. Expert opinion: In the context of bipolar disorder, quetiapine is the only monotherapy approved for the treatment of hypomania/mania, depression and as an adjunctive maintenance therapy. In addition to its antipsychotic properties, this broad mood stabilizing potential may uniquely benefit and simplify the management of some bipolar patients who can tolerate this agent.

A Naturalistic Randomized Placebo-Controlled Trial of Extended-Release Metformin to Prevent Weight Gain Associated With Olanzapine in a US Community-Dwelling Population.

Objective This 24-week pilot study assessed the efficacy, tolerability, and safety of adjunctive metformin versus placebo for the prevention of olanzapine-associated weight gain in community-dwelling adult patients with schizophrenia, schizoaffective disorder, bipolar disorder, or major depression with psychotic features. Methods In a double-blind study, 25 patients were randomly assigned to receive 24 weeks of either olanzapine plus metformin or olanzapine plus placebo. Metformin extended release was titrated to 2000 mg daily as tolerated. No other antipsychotics were allowed, whereas psychotropic medications including antidepressants and mood stabilizers were permitted. The primary outcome measures were change in body weight and homeostatic model assessment for insulin resistance from baseline to week 24. Results The intent-to-treat population comprised patients who had 1 or more post-baseline visit. Mean change in body weight for the olanzapine plus metformin (O/M) group was 5.5 lb, which was less than the 12.8 lb gain for the olanzapine plus placebo (O/P) group (P < 0.05). Compared with O/P group who gained 7% of their body weight, patients in the O/M group gained 3% (P < 0.037). Body mass index change in the O/M group was 0.85 versus 2.02 in the O/P group (P < 0.045). There was a trend for a greater increase in baseline to end point homeostatic model assessment for insulin resistance and waist circumference in the O/P group versus the O/M group. Conclusions In this naturalistic sample of typical US community-dwelling patients, metformin was effective and well tolerated for the prevention of olanzapine-associated weight gain. Adjunctive metformin should be studied in a similar but larger population to determine its role in the prevention of olanzapine-associated weight gain.

Aripiprazole for late-life schizophrenia

Antipsychotics are frequently used in elderly patients to treat a variety of conditions, including schizophrenia. While extensively studied for their impact in younger populations, there is comparatively limited evidence about the effectiveness of these agents in older patients. Further complicating this situation are the high co-morbidity rates (both psychiatric and medical) in the elderly; age-related changes in pharmacokinetics leading to a heightened proclivity for adverse effects; and the potential for multiple, clinically relevant drug interactions. With this background in mind, we review diagnostic and treatment-related issues specific to elderly patients suffering from schizophrenia and other psychotic conditions, focusing on the potential role of aripiprazole.

Therapeutic neuromodulation for treatment of schizophrenia

While antipsychotics are the mainstay of treatment for schizophrenia, many patients do not achieve an adequate response. Indeed, a significant percentage are refractory to medication, including the most effective agent available, clozapine. As a result, there is a need for alternative treatments which are both effective and safe. Therapeutic neuromodulation includes such approaches as electroconvulsive therapy, transcranial magnetic stimulation, transcranial direct current stimulation, and deep brain stimulation and represents a growing field of study for refractory symptoms. This chapter discusses the potential role of such device-based therapies in schizophrenia.

Management of Comorbid Medical Conditions in Schizophrenia

Patients with schizophrenia endure a markedly greater medical disease burden than the general population. In particular, cardiovascular and metabolic diseases are highly prevalent and lead to an increased overall mortality. The causes are multifactorial and include lifestyle factors (e.g., poor dietary habits), obstacles related to health care delivery, and the adverse effects of antipsychotic medications. The role of these various factors on the physical health of patients with schizophrenia and practical approaches to their management are discussed in this chapter, as well as the prevalence and management of non-cardiometabolic diseases, such as cancer and infectious diseases. The role of medication and the impact of these diseases on medication selection are discussed in more detail in Chap. 12.