Faculty Bibliography

Between 1950 and 1969, on a serendipitous basis, psychiatric drug development flourished. However, there has been a steep decline in the development of new medication classes. Instead of new molecular entities, slight molecular modifications producing "me-too" drugs attempted to garner market share. With failing profitability, industry is now withdrawing from psychiatric medication development. Managed care drastically shortened contact between patients and clinicians, so the possible observation of unexpected benefits has been nullified. The randomized, parallel-groups design met FDA requirements for specific pharmacological efficacy. However, it does not determine whether a patient who improved while drug-treated required the drug or would have gotten better on his own. Further, pathophysiology benefit remains obscure. The major psychotropic drugs have no benefits for normal subjects. Their remarkable benefits must stem from a necessary interaction with a pathophysiological state. Therefore, understanding therapeutic benefit by treating normal subjects becomes unlikely. The claim that therapeutic knowledge in psychiatry proceeds from bench to bedside has proven vacuous, primarily because of our limited understanding of brain pathophysiology. The utility of the alternative intensive design for understanding diagnosis, therapeutic benefit, and pathophysiology is emphasized.

In a 12-week randomized open-label trial, adults diagnosed with schizophrenia experiencing inadequate efficacy and/or poor tolerability on risperidone, olanzapine, or aripiprazole were randomized to switch to iloperidone either gradually (ie, down-titration of current therapy over the first 2weeks [to 50% on Day 1, 25% by Week 1, 0% by Week 2]) or immediately. All patients were titrated on iloperidone to 6mg BID by Day 4, then flexibly dosing between 6 and 12mg BID, as needed. The primary variable was the Integrated Clinical Global Impression of Change (I-CGI-C) and the primary analysis time point was Week 12. A total of 500 patients were randomized and received iloperidone (gradual switch, 240; immediate switch, 260), with 175, 155, and 170 patients switched from risperidone, olanzapine, and aripiprazole, respectively. I-CGI-C Results confirmed improved outcomes at Week 12, with scores that were similar between the gradual- and immediate-switch groups, respectively, for risperidone, 2.82 and 2.67 (95% CI: -0.229, 0.511); olanzapine, 2.87 and 3.03 (95% CI: -0.548, 0.235); and aripiprazole, 2.79 and 2.81 (95% CI: -0.405, 0.368). Incidence of adverse events (AEs) was similar in both switch groups, with the most frequently reported (>/=10%) being dizziness, dry mouth, somnolence, and weight increase. In conclusion, switching to iloperidone by either a gradual or an immediate method did not reveal any clinically significant differences in ratings of overall efficacy and safety/tolerability outcomes, based on the I-CGI-C at 12weeks. Similar overall safety/AE profiles were observed regardless of the specific agent from which patients were switched.

PURPOSE: This study examined the clinical significance of switching from olanzapine, quetiapine, or risperidone to aripiprazole by examining changes in predicted risk of cardiovascular disease (CVD) according to the Framingham Risk Score (FRS) and metabolic syndrome status. FRS estimates 10-year risk of "hard" coronary heart disease (CHD) outcomes (myocardial infarction and coronary death) while metabolic syndrome is associated with increased risk of CVD, stroke, and diabetes mellitus. METHOD: Changes in FRS and metabolic syndrome status were compared between patients with BMI >/= 27 and non-HDL-C >/= 130 mg/dL randomly assigned to stay on stable current treatment (olanzapine, quetiapine, or risperidone) or switch to treatment with aripiprazole with 24 weeks of follow-up. All study participants were enrolled in a behavioral program that promoted healthy diet and exercise. RESULTS: The pre-specified analyses included 89 switchers and 98 stayers who had post-baseline measurements needed to assess changes. Least squares mean estimates of 10-year CHD risk decreased more for the switch (from 7.0% to 5.2%) than the stay group (from 7.4% to 6.4%) (p = 0.0429). The odds ratio for having metabolic syndrome (stay vs. switch) at the last observation was 1.748 (95% CI 0.919, 3.324, p = 0.0885). CONCLUSION: Switching from olanzapine, quetiapine, or risperidone to aripiprazole was associated with larger reductions in predicted 10-year risk of CHD than the behavioral program alone. The advantage of switching on metabolic syndrome was not statistically significant. The benefits of switching must be balanced against its risks, which in this study included more discontinuations of the study treatment but no significant increase in symptoms or hospitalizations.

The duration of untreated illness (DUI), meaning the latency to the pharmacological treatment, has been increasingly investigated in the last decade as a predictor of outcome across different psychiatric conditions, particularly in psychotic disorders. DUI is essentially computed by subtracting the age of onset of a specific disorder from the age at which the first adequate pharmacological treatment is administered. Assessment of the latency to treatment represents one of the first steps in planning early interventions. This review examines the role of the DUI in psychotic and affective disorders, focusing on neuropathological, epidemiologic, clinical and prognostic factors related to a longer latency to treatment. Through a Medline and Cochrane Library search, relevant studies up to June 2011 and other pertinent articles including meta-analyses, randomized controlled trials, naturalistic studies and clinical reviews were identified. Converging evidence indicates that a prolonged DUI negatively influences the outcome of first-episode psychosis and schizophrenia in different ways, and increasing data point toward a similar conclusion in affective disorders. Even though methodological limitations related to investigation of the DUI need to be considered, research and interventions aimed to reduce latency to treatments are object of increasing implementation worldwide. The assessment of the DUI represents one of the most important parameters to consider in this perspective, in order to quantify different latency to treatment in specific disorders and to plan related, targeted interventions.

OBJECTIVE: Providing psychiatric consultation to elite athletes presents unique and complex issues. These patients present with multifaceted medical, psychological, and performance concerns. We provide the first report of professional and ethical quandaries that arise in treating elite athletes and ways to address them. METHOD: We identified studies through a MEDLINE search. Search terms included the following, individually and in combination: psychiatry, athletes, elite athletes, professional athletes, sports, sport psychiatry, mental illness, major depressive disorder, depression, bipolar disorder, suicide, anxiety, generalized anxiety disorder, obsessive compulsive disorder, social phobia, social anxiety disorder, panic disorder, post traumatic stress disorder, specific phobia, psychosis, eating disorders, anorexia nervosa, bulimia nervosa, attention deficit hyperactivity disorder, substance abuse, substance dependence, addiction, alcohol, anabolic steroids, stimulants, antidepressants, mood stabilizers, anxiolytics, antipsychotics, sedative-hypnotics, psychotropics, medications, and psychiatric medications. We restricted results to the English language and used no date restrictions. We retrieved all articles discussing psychiatric diagnosis or psychiatric treatment of athletes. We reviewed each article's findings to see if they applied to elite athletes and reviewed the references of each article for additional articles that had been missed in the initial search and that might include findings relevant to the scope of our article. Our search found no controlled data to guide treatment in working with elite athletes. We describe the literature that does exist and present 4 case examples to illustrate diagnostic and treatment issues with elite athletes. RESULTS: Patient and family characteristics are described as they bear on treatment context. The key pitfalls that interfere with treatment are listed, and clinical guidelines to improve outcomes are suggested. Specific key pitfalls that interfere with treatment include elite athletes' expecting "special treatment," issues of flexibility in treatment to accommodate travel schedules and the need for privacy, and inclusion of coaches and significant others in treatment. Recommendations for working with this population include being flexible within reason about timing of sessions, involving family members when relationship issues are involved, and not compromising on delivering the appropriate treatment, including medications and hospitalizations as necessary. CONCLUSIONS: The challenges of treating the elite athlete are great, but successful treatment is possible.

OBJECTIVE: Our aim in this article is 2-fold: first, to examine the mid-term to long-term data on efficacy, from controlled and naturalistic and other studies, in order to determine if they are consistent with the quantitative meta-analyses of mostly short-term, randomized controlled trials Our second (and most important) aim is to use these and other data to provide guidance about the potential relationship of these differences among antipsychotics to the individual patient's own experience with antipsychotic drugs in the process of shared decision-making with the patients and their significant others. DATA SOURCES: A search of PubMed, Embase, and PsychINFO was conducted for articles published in English between January 1, 1999, and April 2011, using the search terms double-blind AND randomized AND olanzapine AND (ziprasidone OR risperidone OR quetiapine OR haloperidol OR fluphenazine OR perphenazine OR aripiprazole). STUDY SELECTION: Studies with a duration 3 months or longer, including patients with schizophrenia or schizoaffective disorder, reporting survival analysis for all-cause discontinuation and relapse or dropout due to poor efficacy were selected. DATA EXTRACTION: We extracted the number of patients relapsed due to poor efficacy and hazard rates for relapses. DATA SYNTHESIS: Overall, the efficacy patterns of both controlled effectiveness and observational long-term studies closely parallel the efficacy observed in the short-term, controlled studies. The results of Phase 1 Clinical Antipsychotic Trials of Intervention Effectiveness are very similar to, but not identical with, the controlled short-term efficacy studies, the European First-Episode Schizophrenia Trial, and naturalistic studies. The mid-term and long-term data suggest that olanzapine is more effective than risperidone and that both of these are better than the other first- and second-generation antipsychotics except for clozapine, which is the most efficacious of all. Further large differences emerged regarding the specific mid-term and long-term safety profiles of individual antipsychotics. CONCLUSIONS: Despite intraclass differences and the complexities of antipsychotic choice, the second-generation antipsychotics are important contributions not only to the acute phase but, more importantly, to the maintenance treatment of schizophrenia.

OBJECTIVE: This study is a post hoc analysis of additions of antidepressants, anxiolytics, and sedative/hypnotics in treatment of patients randomized to antipsychotic treatment in the CATIE study, which recruited a chronic, "real world" schizophrenia sample and followed patients for up to eighteen months. We examined baseline predictors of initiation, time until initiation, and duration of treatment with antidepressants, anxiolytics, and sedative/hypnotics in CATIE study participants. METHODS: Psychotropic medication use by 1,449 CATIE study participants was documented at each study visit. Baseline demographic and clinical predictors of initiation, of time to initiation, and of duration of treatment of Concomitant Psychotropic Medications (CPMs) in each category (antidepressant, anxiolytic, and sedative/hypnotics) were identified through multiple regression analyses. RESULTS: Initiation of new CPMs post baseline by CATIE clinicians was moderately frequent, with 14.6% of patients receiving antidepressants, 13.7% receiving anxiolytics, and 11.2% receiving sedative/hypnotics. Predictors of antidepressant initiation (14.6% of group) were being female or white, and having a prior diagnosis of depression or symptoms of depression at baseline. Patients with higher positive symptom scores and younger patients were started on antidepressants sooner. Duration of antidepressant treatment was longer in patients with less education and in those with a history of alcohol abuse/dependence. Predictors of anxiolytic initiation (13.7% of group) were not being of African-American race, being separated/divorced, younger age, higher body mass index, and akathisia. Time to anxiolytic initiation was shorter in patients who were separated or divorced and in patients with better neurocognitive functioning. Duration of anxiolytic treatment was shorter for African Americans and longer in patients with better instrumental role functioning. Predictors of sedative/hypnotic use (11.2% of group) were depressive symptoms and prior diagnosis of an anxiety disorder. Time to initiation of sedative/hypnotics was longer for those with depressive symptoms and shorter for those with a history of alcohol abuse/dependence. CONCLUSIONS: Sedative/hypnotics, anxiolytics, and antidepressants were commonly used CPMs in schizophrenia during the CATIE trial, where patients were being seen frequently and antipsychotic treatment was optimized. Randomized, controlled clinical trials examining adjunctive use of antidepressants, anxiolytics and sedative/hypnotics to target symptoms of anxiety, depression, and insomnia in patients with schizophrenia are needed to adequately address the efficacy of these interventions.