A neurogenetics approach to understanding individual differences in brain, behavior, and risk for psychopathology.

Neurogenetics research has begun to advance our understanding of how genetic variation gives rise to individual differences in brain function, which, in turn, shapes behavior and risk for psychopathology. Despite these advancements, neurogenetics research is currently confronted by three major challenges: (1) conducting research on individual variables with small effects, (2) absence of detailed mechanisms, and (3) a need to translate findings toward greater clinical relevance. In this review, we showcase techniques and developments that address these challenges and highlight the benefits of a neurogenetics approach to understanding brain, behavior and psychopathology. To address the challenge of small effects, we explore approaches including incorporating the environment, modeling epistatic relationships and using multilocus profiles. To address the challenge of mechanism, we explore how non-human animal research, epigenetics research and genome-wide association studies can inform our mechanistic understanding of behaviorally relevant brain function. Finally, to address the challenge of clinical relevance, we examine how neurogenetics research can identify novel therapeutic targets and for whom treatments work best. By addressing these challenges, neurogenetics research is poised to exponentially increase our understanding of how genetic variation interacts with the environment to shape the brain, behavior and risk for psychopathology.

Pharmacological treatment of schizophrenia: a critical review of the pharmacology and clinical effects of current and future therapeutic agents.

Since the introduction of chlorpromazine and throughout the development of the new-generation antipsychotic drugs (APDs) beginning with clozapine, the D(2) receptor has been the target for the development of APDs. Pharmacologic actions to reduce neurotransmission through the D(2) receptor have been the only proven therapeutic mechanism for psychoses. A number of novel non-D(2) mechanisms of action of APDs have been explored over the past 40 years but none has definitively been proven effective. At the same time, the effectiveness of treatments and range of outcomes for patients are far from satisfactory. The relative success of antipsychotics in treating positive symptoms is limited by the fact that a substantial number of patients are refractory to current medications and by their lack of efficacy for negative and cognitive symptoms, which often determine the level of functional impairment. In addition, while the newer antipsychotics produce fewer motor side effects, safety and tolerability concerns about weight gain and endocrinopathies have emerged. Consequently, there is an urgent need for more effective and better-tolerated antipsychotic agents, and to identify new molecular targets and develop mechanistically novel compounds that can address the various symptom dimensions of schizophrenia. In recent years, a variety of new experimental pharmacological approaches have emerged, including compounds acting on targets other than the dopamine D(2) receptor. However, there is still an ongoing debate as to whether drugs selective for singe molecular targets (that is, 'magic bullets') or drugs selectively non-selective for several molecular targets (that is, 'magic shotguns', 'multifunctional drugs' or 'intramolecular polypharmacy') will lead to more effective new medications for schizophrenia. In this context, current and future drug development strategies can be seen to fall into three categories: (1) refinement of precedented mechanisms of action to provide drugs of comparable or superior efficacy and side-effect profiles to existing APDs; (2) development of novel (and presumably non-D(2)) mechanism APDs; (3) development of compounds to be used as adjuncts to APDs to augment efficacy by targeting specific symptom dimensions of schizophrenia and particularly those not responsive to traditional APD treatment. In addition, efforts are being made to determine if the products of susceptibility genes in schizophrenia, identified by genetic linkage and association studies, may be viable targets for drug development. Finally, a focus on early detection and early intervention aimed at halting or reversing progressive pathophysiological processes in schizophrenia has gained great influence. This has encouraged future drug development and therapeutic strategies that are neuroprotective. This article provides an update and critical review of the pharmacology and clinical profiles of current APDs and drugs acting on novel targets with potential to be therapeutic agents in the future.

Which health-related quality of life aspects are important to patients with chronic myeloid leukemia receiving targeted therapies and to health care professionals? GIMEMA and EORTC Quality of Life Group.

The objective of this study was to investigate the health-related quality of life (HRQOL) aspects valued the most by patients with chronic myeloid leukemia (CML) receiving targeted therapies (TT), and to compare their perception with that of health-care professionals' (HCPs). Semi-structured interviews were conducted with 137 CML patients receiving TT from five different countries. An additional sample of 99 CML patients, completing an online interview, was considered for supportive analyses. A sample of 59 HCPs from 12 countries also participated in the study. Patients and HCPs were asked to rate and rank the importance of a predefined list of 74 HRQOL aspects of potential relevance for CML patients. Patients and HCPs agreed that the following five aspects are most important: fatigue, muscle cramps, swelling, worries, and uncertainty about health condition in the future, and importance of social support in coping with the disease. However, the difference in rankings between the two groups was substantial with respect to other HRQOL aspects investigated. Patients valued some issues related to symptoms much higher than HCPs, thus suggesting that a better symptom management could be the crucial aspects to improve HRQOL of CML patients.

A comparison of preferences of targeted therapy for metastatic renal cell carcinoma between the patient group and health care professional group in South Korea.

OBJECTIVES: To evaluate the preferences of health care professional groups and patient groups with respect to efficacy, adverse events, and administration method for targeted agents of metastatic renal cell carcinoma. METHODS: A total of 485 respondents including cancer patients and health care professionals (medical oncologists, nurses, and pharmacists) were surveyed by using a discrete choice experiment in South Korea. Through a literature review and expert consultation, six attributes--progression-free survival, four adverse events (bone marrow suppression, hand-foot skin reaction, gastrointestinal perforation, and bleeding), and administration--were selected. This study employed the conditional logit regression model. RESULTS: The six attributes are statistically significant for the patient group and health care professional group. The two groups, however, present differences in progression-free survival, hand-foot skin reaction, gastrointestinal perforation, and administration. The relative importance of adverse events is greater for the patient group, while that of efficacy and administration is greater for the health professional group. For doctors, the relative importance of efficacy is as high as 31%, compared with 7% for the patient group. If progression-free survival is prolonged by 1 month, the acceptable level of bone marrow suppression is 1.3% for the patient group and 9.6% for doctors and that of hand-foot skin reaction is 1.0% and 11.8%, respectively, for the patient group and doctors. CONCLUSIONS: This study demonstrates substantial differences in the preference for a targeted drug between the patient group and the health care professional group. Doctors prefer effective and orally administered drugs while patients show more reluctant attitudes about adverse events than do health care professionals.

Regarding the Yin and Yang of Precision Cancer- Screening and Treatment: Are We Creating a Neglected Majority?

In this commentary, we submit that the current emphasis of precision cancer screening and treatment (PCST) has been to provide and interpret the implications of "positive" screening results for those deemed to be at greatest risk for cancer or most likely to benefit from targeted treatments. This is an important, but proportionately small target group, regardless of the cancer context. Overlooked by this focus is the larger majority of those screened who receive "negative" results. We contend that for optimal dissemination of PCST, the complement of positive and negative results be viewed as an inseparable yin-yang duality with the needs of those who receive negative screening results viewed as important as those deemed to be at highest risk or derive targeted treatment benefit. We describe three areas where communication of negative PCST results warrant particular attention and research consideration: population-based family history screening, germline testing for hereditary cancer syndromes, and tumor testing for targeted cancer treatment decision-making. Without thoughtful consideration of the potential for negative results to have psychological and behavioral influences, there is a potential to create a "neglected majority". This majority may be inclined to misinterpret results, disseminate inaccurate information to family, dismiss the credibility of results, or become disillusioned with existing medical treatments.

[Patient's beliefs about oral targeted therapies and impact on drug adherence in lung cancer: A pilot prospective study]. / Croyances des patients envers les thérapies ciblées orales et leur influence sur l'observance dans le cancer broncho-pulmonaire : une étude pilote prospective.

INTRODUCTION: Oral targeted therapies are a new option for lung cancer treatment. However, patient's belief about these drugs - which may interact with adherence - is poorly known in this setting. METHOD: Our study is a pilot prospective unicentric study. Inclusion criteria were: to have been diagnosed with a lung cancer; and to be prescribed with an oral targeted therapy in second line or more. The main objective was to assess patient's specific (SB) and general beliefs (GB) about these drugs according to the Beliefs about Medicines Questionnaire (BMQ). The declared adherence was assessed with the Morisky's test. All included patients underwent a semi-structured interview with a psychologist. RESULTS: Fifthteen patients were included: 12 underwent erlotinib treatment and 3 a crizotinib treatment. The mean score (±standard deviation) at BMQ was 54/85 (±6) overall; 34/50 (±5) for specific belief and 19/35 (±3) for general belief about drugs. During interview, 47% believed in efficacy of targeted oral therapy; 93% reported concerns about their drug; 80% considered that the information given by the physician about the drug was comprehensive; but 40% still required additional information about it. The mean score at Morisky's test was 3/4 (±2) and 53% reported to have forgotten at least once their antineoplastic drug. No correlation was found between belief and adherence. CONCLUSION: Belief about t anti-cancer targeted oral therapy is relatively fair but adherence is moderate in this pilot study. Interview shows the need for additional information about the prescribed drug.

Evaluation of sexuality, health-related quality-of-life and depression in advanced cancer patients: a prospective study in a Phase I clinical trial unit of predominantly targeted anticancer drugs.

BACKGROUND: The advent of molecular targeted agents (MTA) has opened a new era of therapy in oncology. However, some of the toxicities and side-effects of these new drugs are not explored as is the case with the potential impact of MTA on sexuality. This study aimed to prospectively evaluate health-related quality of life (HRQoL), depression and sexual function in advanced cancer patients treated in a Phase I drug unit evaluating MTA. PATIENTS AND METHODS: [corrected] In total, 63 of 74 eligible patients agreed to participate in the study. Four validated self-questionnaires were used: the Medical Outcomes Study Short-Form General Health Survey (SF12), the short form Beck Depression Inventory (BDI), the International Index of Erectile Function (IIEF) and the Female Sexual Function Index (FSFI). Forty-seven patients (75%) responded at baseline and 31 (65%) at 1-month. RESULTS: This is the first evaluation of HRQoL, depression and sexual function in a Phase I drug unit. At baseline, patients had a good mental and physical function despite their disease progression. The response rate was 75% for sexual questionnaires. For 57% of females and 68% of males, quality of sexual life was a subject of interest. After 1-month of treatment, sexual dysfunction included lack of lubrication and comfort in females and erectile dysfunction in males with a statistical association of anti-angiogenic inhibitors in males (p=0.04). CONCLUSIONS: Patients on MTA in Phase I clinical trials had a preserved mental and physical activity whereas their sexual activity declined in both sexes. The impact of MTA on HRQoL and especially sexual function should be routinely assessed in further studies to better understand their potential impact in advanced cancer patients.

Neurosteroids, stress and depression: potential therapeutic opportunities.

Neurosteroids are potent and effective neuromodulators that are synthesized from cholesterol in the brain. These agents and their synthetic derivatives influence the function of multiple signaling pathways including receptors for γ-aminobutyric acid (GABA) and glutamate, the major inhibitory and excitatory neurotransmitters in the central nervous system (CNS). Increasing evidence indicates that dysregulation of neurosteroid production plays a role in the pathophysiology of stress and stress-related psychiatric disorders, including mood and anxiety disorders. In this paper, we review the mechanisms of neurosteroid action in brain with an emphasis on those neurosteroids that potently modulate the function of GABA(A) receptors. We then discuss evidence indicating a role for GABA and neurosteroids in stress and depression, and focus on potential strategies that can be used to manipulate CNS neurosteroid synthesis and function for therapeutic purposes.

My brain made me do it, and my gut didn't help.

Decisions about what, when and how much to eat are made by the brain, though these choices can be strongly influenced by the hedonic and rewarding properties of sweet or fatty foods. The rumbling before and the fullness after eating tells us that the gut also has an important role in the initiation and termination of feeding. Gut-derived peptides continually convey homeostatic information to the brain to guide feeding. These circulating signals can also modify the pleasure and reward associated with food.