Antipsychotic Drug Therapies: Matching primary care practice to clinical challenges

1Associate Professor, Charles E. Schmidt College of Medicine, Florida Atlantic University, United States 2Professor and Program Director, Psychiatry Residency, Charles E. Schmidt College of Medicine, Florida Atlantic University, United States 3Associate Professor and Chief of Family Medicine, Charles E. Schmidt College of Medicine, Florida Atlantic University, United States 4First Sir Richard Doll Professor & Senior Academic Advisor to the Dean, Charles E. Schmidt College of Medicine, Florida Atlantic University, 2800S Ocean Blvd, PHA, Boca Raton, FL 33432, United States


Summary
Primary health care providers prescribe over 50 percent of drug therapies for patients with mental health issues in the United States. Nonetheless, primary health care providers tend to be reluctant to prescribe antipsychotic drug therapies despite their widespread availability and favorable benefi tto-risk ratio. This may be due, at least in part, to appropriate concerns about the serious adverse effects of all earlier fi rst generation, or typical, as well as many of the earlier second generation, or atypical, antipsychotic drug therapies.
In patients with severe mental illness, the totality of evidence supports the wider prescription of newer second and third generation atypical antipsychotic drug therapies.
These drugs tend to have greater clinical effi cacy as well as fewer adverse effects, especially on weight and associated metabolic consequences. The more widespread and appropriate prescription of these drugs by primary health care providers would likely improve the quality of life as well as the markedly reduced lifespan of patients with severe mental illness.
At present, the evidence from randomized trials is insuffi cient to draw fi rm conclusions about benefi ts and risks in nonpsychotic anxiety and behavioral symptoms of dementia.
Thus, primary health care providers should make individual clinical judgments based on the available evidence for each of their patients.
Primary health care providers are the backbone of the healthcare delivery system in the United States (US). As part of their overall focus on a person's health and wellness, they are playing an increasingly important role in identifying as well as treating mental disorders [1]. Primary health care providers prescribe over 50 percent of drug therapies for patients with mental health issues in the US. In addition, about 25 percent of all primary health care patients have diagnosable mental disorders [2]. Both these percentages are likely to increase in the US as there is also an increasing shortage of psychiatrists Many, if not, most primary health care providers are reluctant to prescribe antipsychotic drug therapies despite their widespread availability and favorable benefi t-to-risk ratio. This may be due, at least in part, to appropriate concerns about the serious adverse effects of all earlier fi rst generation, or typical, as well as many earlier second generation, or atypical, antipsychotic drug therapies [4], This Special Report provides recent evidence for primary health care providers which has the potential to change practice patterns by increasing their prescription of antipsychotic drug therapies to those with severe mental illness as well as, perhaps to a wider range of their patients with other disorders such as nonpsychotic anxiety and behavioral symptoms of dementia.
Antipsychotic drug therapies are approved by the US Food and Drug Administration (FDA) to treat acute psychoses, as well as to manage several manifestations of severe mental illness, including schizophrenia and bipolar disorder. They are also used as adjunctive drug therapies with antidepressants in major depressive disorders. Antipsychotic drug therapies were initially divided into two classes, fi rst and secondgeneration [5,6]. The fi rst generation, or typical, antipsychotic drug therapies, are far older, having been fi rst approved by the US FDA in the late 1950s. The earlier second generation, or atypical antipsychotic drug therapies, namely risperidone and quetiapine, were approved by FDA in 1994 and 1997, respectively. The most recent second generation drug to be approved by FDA was cariprazine in 2015 (Table 1).
illness are cigarette smokers compared with about 15% of the general population [8]. Further, patients with severe mental illness when compared to the general population, whether in primary or secondary prevention of coronary heart disease, are signifi cantly less likely to be prescribed drug therapies of proven benefi t, including aspirin, statins, beta-blockers and angiotensin converting enzyme inhibitors or blockers. Finally, even when prescribed these drugs such patients have lower adherence. Thus, there is less access to as well as utilization of medical care of life saving benefi ts. As a consequence of all these factors, such patients have a markedly reduced lifespan, on average 15 to 25 years less than the general population [9].
Coronary heart disease is, far and away, their leading cause of premature death despite the fact that patients with severe mental illness have a tenfold higher lifetime risk of suicide of 10% compared with the general population rate of about 1%. All these considerations support the need for primary health care providers to prescribe atypical antipsychotic drug therapies that do not further exacerbate the already high prevalence of the adverse metabolic risk factor profi le of either primary prevention subjects or secondary prevention patients, both of whom are at markedly increased risks for premature cardiovascular disease events and death [8,9].
Fortunately, a recent refi nement of second generation antipsychotics with differing neurotransmitter profi les has led to the introduction of the term third generation antipsychotics to describe aripiprazole in 2002 and brexpiprazole in 2015 (Table 1). While aripripazole has been far more widely studied, both these third generation antipsychotic drug therapies have comparable effi cacy to second generation atypical antipsychotic drugs and produce far fewer adverse metabolic consequences than earlier agents in the class [5,6].

The Clinical Antipsychotic Trials of Intervention
Effectiveness [10], tested some, but not all, of the earlier second generation antipsychotic drugs, including olanzapine, quetiapine, risperidone and ziprasidone. One primary outcome was weight gain over an 18-month period in patients with chronic schizophrenia treated for an average of more than 14 years. Olanzapine, quetiapine and risperidone all produced signifi cant weight gain. In fact, olanzapine produced the most weight gain of about 36 pounds, compared to quetiapine, which produced weight gain of about 9 pounds and risperidone, which produced weight gain of about 7 pounds. In contrast, patients assigned at random to ziprasidone, lost about 5 pounds. Thus, the majority of these earlier second generation antipsychotic drug therapies produced severe metabolic consequences which further increased the already adverse cardiovascular risk profi le of patients with severe mental illness. For example, the most frequently prescribed antipsychotic drug in the United States and many other countries has been quetiapine [11], which produces adverse metabolic effects [10]. In contrast, it is also notable that for bipolar I depression alone or as adjunctive therapy, lurasidone, a newer second generation antipsychotic drug with minimal metabolic effects, has been approved for bipolar and mixed depressive disorders, in addition to its prior indication for the treatment of chronic schizophrenia [6].  Recently, randomized evidence has been published for what has been termed the third generation atypical antipsychotic drugs, especially aripiprazole, with comparable effi cacy and more favorable weight and metabolic side effect profi les [5,6] ( Table 1). In addition, aripiprazole is recommended for the treatment of schizophrenia as well as for the acute treatment of manic and mixed episodes of bipolar I disorder, and for agitation associated with either of these disorders. Further, patients with chronic schizophrenia can be successfully switched from an older second generation antipsychotic drug with metabolic consequences such as olanzapine or quetiapine to a newer second generation drug such as lurasidone or third generation drug such as aripiprazole, without detrimental effects. In one randomized trial, patients with schizophrenia and metabolic syndrome were assigned to aripiprazole or continued on olanzapine. Those allocated at random to aripiprazole experienced signifi cant decreases in body weight, dyslipidemia, hypertension, and insulin resistance leading to diabetes. Thus, a large proportion of patients who were switched at random from olanzapine to aripiprazole had decreases in the severity or even continued occurrence of their metabolic syndrome [12].
In addition to their recommended use in severe mental illness, the availability of newer second generation and third generation antipsychotic drugs with fewer metabolic consequences, has raised consideration of their possible favorable benefi t-to-risk ratio for other non-psychotic but persistent, disabling and refractory conditions, including anxiety [13], and behavioral symptoms of dementia [14], For example, aripiprazole has been shown to have effi cacy in refractory generalized anxiety and could potentially play a role in the treatment of various anxiety disorders, either alone or as adjunctive therapy with antidepressants [13]. It should also be noted that one major concern for the treatment of the behavioral symptoms in elderly patients with dementia with second generation antipsychotic drug therapies derived initially from adverse event reports to the US FDA [15]. This led to the formulation of the hypothesis that atypical antipsychotics increase the risks of stroke and mortality in elderly patients with dementia and resulted in a black box warning. In this regard, it is important to note that adverse event reports have no comparison group so they are useful to formulate but not to test hypotheses. Thus, the alternative hypothesis of no association was also plausible due to uncontrolled and uncontrollable confounding due to severity of illness and preexisting health conditions, which has been termed confounding by indication [16]. The most reliable design strategy to test the most plausible small to moderate effects is a large scale randomized trial [17].
In this regard, the Clinical Antipsychotic Trials of Intervention Effectiveness tested the hypothesis in elderly patients with Alzheimer's disease and dementia. Patients assigned at random to olanzapine, quetiapine, and risperidone. all of which produce serious adverse effects on weight and associated metabolic consequences, had increased risks of mortality [18], With respect to aripiprazole, however, which is less likely to produce weight gain and associated metabolic consequences, randomized data suggested net benefi ts [19].  has an investment management relationship with the West-Bacon Group within SunTrust Investment Services, which has discretionary investment authority; does not own any common or preferred stock in any pharmaceutical or medical device company.