Jacob S. Ballon

Signaling pathways in schizophrenia: emerging targets and therapeutic strategies

Dopamine D(2) receptor antagonism is a unifying property of all antipsychotic drugs in use for schizophrenia. While often effective at ameliorating psychosis, these drugs are largely ineffective at treating negative and cognitive symptoms. Increasing attention is being focused on the complex genetics of the illness and the signaling pathways implicated in its pathophysiology. We review targeted approaches for pharmacotherapy involving the glutamatergic, GABAergic and cholinergic pathways. We also describe several of the major genetic findings that identify signaling pathways representing potential targets for novel pharmacological intervention. These include genes in the 22q11 locus, DISC1, Neuregulin 1/ErbB4, and components of the Akt/GSK-3 pathway.

Aerobic fitness and body mass index in individuals with schizophrenia: Implications for neurocognition and daily functioning

Previous reports indicate that among healthy individuals low aerobic fitness (AF) and high body-mass index (BMI) predict poor neurocognition and daily-functioning. It is unknown whether these associations extend to disorders characterized by poor neurocognition, such as schizophrenia. Therefore, we compared AF and BMI in individuals with schizophrenia and non-clinical controls, and then within the schizophrenia group we examined the links between AF, BMI, neurocognition and daily-functioning. Thirty-two individuals with schizophrenia and 64 gender- and age-matched controls completed assessments of AF (indexed by VO2max) and BMI. The former also completed measures of neurocognition, daily-functioning and physical activity. The schizophrenia group displayed significantly lower AF and higher BMI. In the schizophrenia group, AF was significantly correlated with overall neurocognition (r=0.57), along with executive functioning, working memory, social cognition, and processing speed. A hierarchical regression analysis indicated that AF accounted for 22% of the neurocognition variance. Furthermore, AF was significantly correlated with overall daily-functioning (r=0.46). In contrast, BMI displayed significant inverse correlations with neurocognition, but no associations to daily-functioning. AF was significantly correlated physical activity. The authors discuss the potential use of AF-enhancing interventions to improve neurocognitive and daily-functioning in schizophrenia, along with putative neurobiological mechanisms underlying these links, including Brain-Derived Neurotrophic Factor.

Molecular pathophysiology of metabolic effects of antipsychotic medications

Antipsychotic medications are associated with major metabolic changes that contribute to medical morbidity and a significantly shortened life span. The mechanisms for these changes provide us with a broader understanding of central nervous and peripheral organ-mediated metabolic regulation. This paper reviews an extensive literature regarding putative mechanisms for effects of antipsychotic medications on weight regulation and glucose homeostasis as well as potential inherent metabolic risks of schizophrenia itself. We present a model suggesting that peripheral antipsychotic targets play a critical role in drug-induced weight gain and diabetes. We propose that a better understanding of these mechanisms will be crucial to developing improved treatments for serious mental illnesses as well as providing potentially novel therapeutic targets of metabolic disorders including diabetes.

Polypharmacy for schizophrenia.

Purpose of review Combining psychotropic medications is common for people diagnosed with schizophrenia facing a variety of clinical circumstances. This review provides an update on evidence regarding the effectiveness of polypharmacy approaches. Recent findings Epidemiology studies have demonstrated that polypharmacy is extremely common, but evidence regarding all polypharmacy approaches for schizophrenia from randomized controlled trials remains scarce. Combinations of antipsychotic medicines are unsupported by evidence. Antidepressants are commonly used to treat depressive symptoms; this logical role for antidepressants has little support from randomized controlled trials (RCTs) but may be associated with lower suicide and all-cause mortality. Insufficient evidence supports the use of benzodiazepines for schizophrenia; possible risks of benzodiazepines, including increased mortality rates revealed in observational studies, warrant caution and further study. Summary The lack of evidence regarding common treatment strategies exacerbates the tremendous challenge of providing optimal pharmacotherapy for individuals with schizophrenia. Comparative effectiveness research, using observational methods when appropriate and RCTs when possible, is needed to inform clinical practice, use resources wisely and improve outcomes.

Aerobic exercise for cognitive deficits in schizophrenia — The impact of frequency, duration, and fidelity with target training intensity

Individualswith schizophrenia display substantial deficits in cognitive functioning (Green et al., 2004) for which available treatments offer only limited benefits. Recent reports have indicated that aerobic exercise (AE) leads to improvements in both aerobic fitness (AF; Vancampfort et al., 2015; Armstrong et al., submitted for publication) and cognitive functioning among individual with schizophrenia (Kimhy et al., 2015; Kimhy et al., 2014). A recent review of trials examining exercise interventions in people with schizophrenia have suggested that clinical benefits from such trials are related to the dose of exercise, with interventions employing at least 90min of moderate-to-vigorous exercise per week result in clinical improvements (i.e., Firth et al., 2015). However, the specific AE training characteristics that contribute to cognitive improvements remain largely unknown. To address this issue, we examined the impact of frequency, duration, and fidelity with target training intensity on changes in cognition in 13 individuals with schizophrenia (average age = 36.31, SD = 11.16; 38% female) who completed an AE training program as part of a single-blind randomized clinical trial examining the impact of AE on cognition (Kimhy et al., 2015). Detailed descriptions of the trial and the AE procedures have been published elsewhere (Kimhy et al., 2015; Kimhy et al., in press). Briefly, the AE program was informed by the American College of Sports Medicine and federal guidelines for the frequency, intensity, time, and type of AE (US Department of Health and Human Services, 2008). The program involved three one-hour AE sessions/week over 12 weeks. The sessions opened with a 10-min warm-up period, after which participants exercised individually for 45 min, ending with a 5-min cool-down period. A trainer was present during the AE sessions for guidance and support, along with a research assistant who collected behavioral data. Changes in cognitive functioning from baseline to 12 weeks were indexed by changes in the composite scores of the MATRICS Consensus Cognitive Battery. Additionally, at baseline participants completed a cardiopulmonary exercise test (CPET) to determine their AF (VO2 peak; ml/kg/min) and maximal heart rate (HRmax). The latter was used to determine the in-session target AE training intensity for each participant. Targets were set to 60% of HRmax in week 1, 65% in week 2, 70% in week 3, and 75% in weeks 4–12. The AE intensity was indexed by the in-session heart rate recorded using Polar RS400 heart rate monitors (Polar Electro Inc., Lake Success, NY) worn by participants during sessions. The monitors were programmed to emit a soft beep if a participants heart rate fell below the individually-targeted AE intensity level for a particular week of training. On such occasions, the trainer encouraged the participant to achieve their target goal. Following the completion of the 12-week training program, all participants completed a second CPET to determine changes in AF.

Emotional granularity and social functioning in individuals with schizophrenia: An experience sampling study

Previous research has shown that healthy individuals who fail to differentiate among emotional states (i.e., those with low emotional granularity; EG) have poorer social functioning (SF) than those with high EG. It is unknown, however, whether these associations extend to clinical disorders characterized by impaired SF, such as schizophrenia. In the present study, we compared SF and EG in individuals with schizophrenia and healthy controls, and then, within the schizophrenia group, we examined the links between EG and SF. Employing an Experience Sampling Method approach, 77 individuals with schizophrenia and 27 healthy controls rated their momentary emotions (sadness, anxiety, anger, and happiness) up to 10 times/day over a two-day period using mobile electronic devices. For each participant, we then calculated the within-subject average correlations among the momentary emotion ratings, producing two EG indices - EGIall for all emotions and EGIneg for negative ones. A subsample of participants with schizophrenia also completed self-report, interview, and ability-based measures of SF. Compared to healthy controls, individuals with schizophrenia displayed significantly poorer SF and lower EGIall, but comparable EGIneg. Within the schizophrenia group, hierarchical multiple regression analyses indicated that EGIall, but not EGIneg, significantly predicted social dysfunction after controlling for emotional awareness, symptoms, and emotional intensity and variability. Our findings indicate that individuals with schizophrenia have a relatively intact ability to differentiate among negative emotions in everyday life. However, they experience significant difficulties differentiating between positive and negative emotions, and this may contribute to their social difficulties.

Use of Active-Play Video Games to Enhance Aerobic Fitness in Schizophrenia: Feasibility, Safety, and Adherence

OBJECTIVE Active-play video games have been used to enhance aerobic fitness in various clinical populations, but their use among individuals with schizophrenia has been limited. METHODS Feasibility, acceptability, safety, and adherence data were obtained for use of aerobic exercise (AE) equipment by 16 individuals with schizophrenia during a 12-week AE program consisting of three one-hour exercise sessions per week. Equipment included exercise video games for Xbox 360 with Kinect motion sensing devices and traditional exercise equipment. RESULTS Most participants (81%) completed the training, attending an average of 79% of sessions. The proportion of time spent playing Xbox (39%) exceeded time spent on any other type of equipment. When using Xbox, participants played 2.24±1.59 games per session and reported high acceptability and enjoyment ratings, with no adverse events. CONCLUSIONS Measures of feasibility, acceptability, adherence, and safety support the integration of active-play video games into AE training for people with schizophrenia.

The impact of aerobic exercise training on cardiopulmonary functioning in individuals with schizophrenia

Low aerobic fitness is ubiquitous among individuals with schizophrenia (Kimhy et al., 2014; Strassnig et al., 2011) and is linked to a wide range of cardiopulmonary and metabolic problems (Vancampfort et al., 2015a; Vancampfort et al., 2015b). However, previous reports examined only a limited range of exercise parameters, primarily VO2max or VO2peak (Heggelund et al., 2011; Vancampfort et al., 2015b). Thus, our aimwas to examine the impact of aerobic exercise (AE) training onmultiple parameters of exercise capacity including heart rate (HR), respiratory exchange ratio (RER), resting and peak systolic and diastolic blood pressure (SBP, DBP), absolute peak oxygen uptake (VO2mL/kg/min), peakminute ventilation (VE), peak tidal volume (Vt), end tidal carbon dioxide pressure (PetCO2), rate of carbon dioxide production at peak (VCO2 L/min), and peak work rate (watts). Participants also completed a 6MWT (ATS Statement, 2002). Employing a single-blind, randomized clinical trial design, participants were randomized to receive 12 weeks of Treatment-as-Usual (TAU) or attend AE training, in addition to TAU. Detailed inclusion and

Teaching pearls from the lost art of psychopharmacology.

Rapid advances in neuroscience and clinical research have made the practice of quality clinical psychopharmacology increasingly difficult. While practice guidelines, model psychopharmacology curricula, and clinical algorithms have helped “the science” of psychopharmacology, they often fail to provide guidance for clinicians in specific clinical situations with individual patients. Quality psychopharmacology practice is based on a combination of knowledge, experience, judgment, and luck. In this article, the authors present their collection of psychopharmacology “pearls” for trainees as well as experienced clinicians. (Journal of Psychiatric Practice 2009;15:423–426)

Pathophysiology of drug induced weight and metabolic effects: findings from an RCT in healthy volunteers treated with olanzapine, iloperidone, or placebo

Second generation antipsychotics are prescribed for an increasing number of psychiatric conditions, despite variable associations with weight gain, dyslipidemia, and impaired glucose tolerance. The mechanism(s) of the apparent causal relationships between these medications and metabolic effects have been inadequately defined and are potentially confounded by genetic risk of mental illness, attendant lifestyle, and concomitant medications. Therefore, we conducted a study in which 24 healthy volunteers were randomized to olanzapine (highly weight-gain liability), iloperidone (less weight-gain liability), or placebo treatment for 28 days under double-blind conditions. We hypothesized that antipsychotics induce weight gain primarily through increased caloric intake, which causes secondary dyslipidemia and insulin resistance. Subjects were phenotyped pre- and post-treatment for body weight, adiposity by dual energy X-ray absorptiometry, energy expenditure by indirect calorimetry, food intake, oral glucose tolerance, plasma lipids, glucose, insulin, and other hormones. We found significantly increased food intake and body weight but no change in energy expenditure in olanzapine-treated subjects, with associated trends towards lipid abnormalities and insulin resistance the extent of which were presumably limited by the duration of treatment. Iloperidone treatment led to modest non-significant and placebo no weightgain, lipid increases and alterations in insulin metabolism. We conclude that second generation antipsychotic drugs, as represented by olanzapine, produce their weight and metabolic effects, predominantly, by increasing food intake which leads to weight gain that in turn induces metabolic consequences, but also through other direct effects on lipid and glucose metabolism independant of food intake and weight gain.