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Imaging genetics provides a unique tool with which to explore and evaluate the functional impact of brain-relevant genetic polymorphisms with the potential to understand their impact on behavior. Because statistical association with clinical diagnosis does not establish biological significance nor identify a mechanism of risk, imaging genetics is a uniquely valuable strategy for extending statistical evidence with biological data. Applications include identifying biologic mechanisms and pathways that mediate individual differences in complex behaviors and vulnerability to disease, and conversely identifying genes that contribute to functional variation in brain circuitry. Additionally, neuroimaging genetics can validate data that suggest an association with psychiatric illness as well as providing evidence of the mechanism of risk. This review also outlines several critical principles of imaging genetics including a rational approach to the selection of candidate genes, the selection of task paradigms that could be plausibly linked to the biology of the gene of interest, and careful control of non-genetic factors. The future of imaging genetics holds great promise for brain research and for biologic validation of genetic validation in CNS disorders, but a disciplined application of the basic principles outlined in this review is critical.

Variability in serotonin (5-HT) function is associated with individual differences in normal mood and temperament, as well as psychiatric illnesses, all of which are influenced by amygdala function. This study evaluated the acute effects of 5-HT reuptake blockade on amygdala function using pharmacological functional MRI. Eight healthy men completed a double-blind balanced crossover study with the selective 5-HT reuptake inhibitor, citalopram (20 mg infused over 30 min), and normal saline. Amygdala reactivity in response to novel facial expressions was assessed on three successive scans, once before drug/placebo infusion, once early in the infusion, and once at the end of infusion. Acute citalopram administration resulted in concentration-dependent increases in human amygdala reactivity to salient stimuli. The current pattern of 5-HT-mediated amygdala reactivity may represent an important pathway through which SSRIs achieve an antidepressant effect. Intriguingly, our data may also reveal a mechanism contributing to clinical observations of extreme agitation, restlessness, and suicidal ideation in some individuals during acute SSRI treatment. Developing a comprehensive model of how 5-HT modulates human amygdala reactivity supporting behavioral and physiological arousal will be instrumental for our understanding of basic neurobehavioral processes, their dysfunction in psychiatric illnesses, and their contribution to mechanism of treatment response.

The L-type calcium channel gene, CACNA1C, is a validated risk gene for schizophrenia and the target of calcium channel blockers. Carriers of the risk-associated genotype (rs1006737 A allele) have increased frontal cortical activity during working memory and higher CACNA1C mRNA expression in the prefrontal cortex. The aim of this study was to determine how the brain-penetrant calcium channel blocker, nimodipine, changes brain activity during working memory and other cognitive and emotional processes. We conducted a double-blind randomized cross-over pharmacoMRI study of a single 60 mg dose of oral nimodipine solution and matching placebo in healthy men, prospectively genotyped for rs1006737. With performance unchanged, nimodipine significantly decreased frontal cortical activity by 39.1% and parietal cortical activity by 42.8% during the N-back task (2-back > 0-back contrast; P FWE  < 0.05; n  = 28). Higher peripheral nimodipine concentrations were correlated with a greater decrease in activation in the frontal cortex. Carriers of the risk-associated allele, A ( n  = 14), had a greater decrease in frontal cortical activation during working memory compared to non-risk allele carriers. No differences in brain activation were found between nimodipine and placebo for other tasks. Future studies should be conducted to test if the decreased cortical brain activity after nimodipine is associated with improved working memory performance in patients with schizophrenia, particularly those who carry the risk-associated genotype. Furthermore, changes in cortical activity during working memory may be a useful biomarker in future trials of L-type calcium channel blockers.

Although geriatric patients are the major recipients of drugs, most research during drug development is conducted in healthy younger adults. Safe and effective drug therapy in the elderly requires an understanding of both drug disposition and response in older individuals. One of the major issues in studying the elderly relates to the ability to study a large number of people in a minimally invasive way. Population pharmacokinetics can be used to model drug concentrations from a large population of sparsely sampled individuals. Population pharmacokinetics characterizes both the interindividual (between-subject) and intraindividual (within-subject) variability, and can identify factors that contribute to pharmacokinetic and pharmacodynamic variability. Population pharmacokinetics can be used to aid in designing large clinical trials by simulating virtual data based on the study design. It can also be used to assess consistency of drug exposure and evaluate its effect on clinical outcome. This article reviews the methods used in pharmacokinetic modeling, as well as providing examples of population pharmacokinetic modeling, highlighting its application to geriatric psychiatry.

The antipsychotic drug, olanzapine, one of the most widely used drugs in clinical medicine, has a high rate of discontinuation due to inefficacy and/or adverse effects. We identified a single nucleotide polymorphism in the drug metabolizing enzyme, cytochrome P450 3A43 (CYP3A43; rs472660), that highly significantly predicted olanzapine clearance in the Clinical Antipsychotic Trials of Intervention Effectiveness trial ( P =5.9e −7 ). Moreover, at standard antipsychotic doses, 50% of individuals with the high clearance genotype (AA) have trough blood levels below the therapeutic range. Interestingly, a much higher proportion of African Americans carry the A allele compared with Caucasians (allele frequency 67 vs 14%). After accounting for CYP3A43 genotype, race is no longer a significant predictor of olanzapine clearance. Olanzapine clearance was associated with measures of clinical response. Patients with greater clearance had higher symptom ratings and were more likely to discontinue treatment due to an inadequate response. Our data identify a genetic mechanism for variation in olanzapine response and demonstrate that blood level monitoring of olanzapine treatment is advisable.

Although much is known about the role of serotonin (5-HT) in the pathophysiology of depression, little is known about the temporal and regional brain alterations in 5-HT as they relate to the treatment of depression and anxiety. This study aimed to evaluate the acute effects of the selective serotonin reuptake inhibitor (SSRI), citalopram, on neuronal activation elicited during an emotional task using functional MRI (fMRI) in healthy subjects. Eight healthy men completed the double-blind placebo-controlled crossover study of citalopram (20 mg infused over 30 min) and normal saline. Subjects performed the emotional task once before drug/placebo infusion (Faces 1) and twice during drug/placebo infusion, once early in the infusion (Faces 2) and once at the end of infusion (Faces 3). A main effect of task was found in the L and R amygdala. A cluster in the right amygdala had increased activation for the Faces 2 task during the citalopram infusion, compared to the baseline Faces 1 task. An even greater bilateral amygdala response to citalopram was found at the end of infusion (Faces 3), when the citalopram concentrations approach their maxima, compared to the baseline Faces 1 task. This suggests that acute citalopram administration potentiates the amygdala response to emotional stimuli. An exploratory analysis was done using serotonin transporter genotype as a covariate. S allele carriers (2 s/s and 3 s/l) had a greater baseline amygdala response than l/l (n=3) homozygotes. However l/l homozygotes had a greater response to citalopram, comparing the Faces 3 to the Faces 1 task. This study generated the first in vivo human data regarding the regional effects of acute intravenous SSRI administration on affective task-related neuronal activation. An understanding of the regional effects of SSRIs may aid in understanding the mechanism by which these agents produce their therapeutic effects. By including 5-HTTLPR genotype in the analyses, we may account for some of the variability in response to citalopram and other SSRIs. These efforts contribute to the identification of biological mechanisms and pathways that mediate response to SSRIs, and contribute to our understanding of individual differences in complex behaviors and vulnerability to psychiatric illnesses.

A primer on understanding the influence of specific genetic variants on cognition, affective regulation, personality, and central nervous system disorders. It has long been known that aspects of behavior run in families; studies show that characteristics related to cognition, temperament, and all major psychiatric disorders are heritable. This volume offers a primer on understanding the genetic mechanisms of such inherited traits. It proposes a set of tools—a conceptual basis—for critically evaluating recent studies and offers a survey of results from the latest research in the emerging fields of cognitive genetics and imaging genetics. The chapters emphasize fundamental issues regarding the design of experiments, the use of bioinformatic tools, the integration of data from different levels of analysis, and the validity of findings, arguing that associations between genes and cognitive processes must be replicable and placed in a neurobiological context for validation. The Genetics of Cognitive Neuroscience aims to give the reader a working understanding of the influence of specific genetic variants on cognition, affective regulation, personality, and central nervous system disorders. With its emphasis on general methodological points, it will remain a valuable resource in a fast-evolving field. Contributors Kristin L. Bigos, Katherine E. Burdick, Jingshan Chen, Aiden Corvin, Jeffrey L. Cummings, Ian J. Deary, Gary Donahoe, Eco J. C. de Geus, Jin Fan, Erika E. Forbes, John Fossella, Terry E. Goldberg, Ahmad R. Hariri, Lucas Kempf, Anil K. Malhotra, Venkata S. Mattay, Lauren M. McGrath. Kristin K. Nicodemus, Francesco Papaleo, Bruce F. Pennington, Michael I. Posner, Danielle Posthuma, John M. Ringman, Shelley D. Smith, Daniel R. Weinberger, Fengyu Zhang

Safe, effective drug therapy in older adults requires an understanding of drug disposition and response in this population. Evidence suggests that physiologic changes during aging, including hepatic or renal function changes, contribute to pharmacokinetic differences. A major issue surrounding the study of older adults relates to the ability to study a large number of people in a minimally invasive way. Population pharmacokinetics provides a potential means of addressing this issue and a tool to evaluate drug exposure’s magnitude and consistency. This article highlights examples of pharmacokinetic studies in psychiatry, in particular those conducted in older adults. It also reviews new drugs approved for treatment in psychiatry or neurology, many of which were developed as novel formulations (eg, extended-release transdermal film) with improved pharmacokinetic profiles or developed with regard to the actions of a specific enantiomer or metabolite.