Imaging genetics: implications for research on variable antidepressant drug response

Genetic variation of SLC6A4, HTR1A, MAOA, COMT and BDNF has been associated with depression, variable antidepressant drug responses as well as impacts on brain regions of emotion processing that are modulated by antidepressants. Pharmacogenetic studies are using psychometric outcome measures of drug response and are hampered by small effect sizes that might be overcome by the use of intermediate endophenotypes of drug response, which are suggested by imaging studies. Such an approach will not only tighten the relationship between genes and drug response, but also yield new insights into the neurobiology of depression and individual drug responses. This article provides a comprehensive overview of pharmacogenetic, imaging genetics and drug response studies, utilizing imaging techniques within the context of antidepressive drug therapy.     

Mathematical Formalism for the Properties of Four Basic Models of Indirect Pharmacodynamic Responses

Four basic models for characterizing indirect pharmacodynamic responses were proposed previously and applied using differential equations. These models consider inhibition or stimulation by drug of the production or loss of mediators or response variables. This report develops partially integrated solutions for these models which allow more detailed examination of the roles of model parameters and pharmacokinetic functions in affecting the time course of drug effects. Because of the nonlinear Hill function, the solutions are represented by means of definite integrals containing kinetic and dynamic functions. These solutions allow a qualitative examination, using calculus, of how response is controlled by Dose. IC₅₀ or SC₅₀, I_max or S_max, and k_out for drugs exhibiting monotonic or biphasic disposition. Characteristics of the response curves that were identified include shape, maximum or minimum, and changes with the above parameters and time. These relationships, together with simulation studies, provide a fundamental basis for understanding the temporal aspects of the basic indirect response models.     

High-throughput fluorescence imaging approaches for drug discovery using in vitro and in vivo three-dimensional models

Introduction: High-resolution microscopy using fluorescent probes is a powerful tool to investigate individual cell structure and function, cell subpopulations and mechanisms underlying cellular responses to drugs. Additionally, responses to drugs more closely resemble those seen in vivo when cells are physically connected in three-dimensional (3D) systems (either 3D cell cultures or whole organisms), as opposed to traditional monolayer cultures. Combined, the use of imaging-based 3D models in the early stages of drug development has the potential to generate biologically relevant data that will increase the likelihood of success for drug candidates in human studies.

Areas covered: The authors discuss current methods for the culturing of cells in 3D as well as approaches for the imaging of whole-animal models and 3D cultures that are amenable to high-throughput settings and could be implemented to support drug discovery campaigns. Furthermore, they provide critical considerations when discussing imaging these 3D systems for high-throughput chemical screenings.

Expert opinion: Despite widespread understanding of the limitations imposed by the two-dimensional versus the 3D cellular paradigm, imaging-based drug screening of 3D cellular models is still limited, with only a few screens found in the literature. Image acquisition in high throughput, accurate interpretation of fluorescent signal, and uptake of staining reagents can be challenging, as the samples are in essence large aggregates of cells. The authors recognize these shortcomings that need to be overcome before the field can accelerate the utilization of these technologies in large-scale chemical screens.     

Effects of scopolamine on shuttle-box avoidance and go-no go discrimination: Response-stimulus relationships,pretreatment baselines,and repeated exposure to drug

Summary The effects of scopolamine on shuttle-box avoidance and go-no go discrimination in pretrained rats have been shown to vary as a function of performance baselines, of response-CS (or response-S⁺) relationships, and of previous experience in the drug condition. Scopolamine induced a slight depression of active avoidance responding in rats with high baselines when the CS was terminated by the response, while a significantly greater depression was observed when a CS of fixed duration was not immediately terminated by the response. Animals with low baselines were significantly facilitated by the drug when the CS was terminated by the response, but not when it had a fixed duration.As concerns go-no go discrimination, the overall impairment of performance provoked by scopolamine was about the same with a fixed or a variable duration of the S⁺. However, the impairment consisted entirely of an increase of errors of commission (punished crossing responses to S^–) when the S⁺ was terminated by the response. Both errors of commission and errors of omission (absence of response to S⁺) increased after treatment when the S⁺ had a fixed duration.The differences between the two groups of animals increased with repeated exposure to drug. In the group performing with an S⁺ of fixed duration the suppression of responses to S^– was often accompanied by a further marked increase of errors of omission. With repeated exposure most animals gradually compensated for the performance deficit induced by scopolamine in the go-no go situation. Repeated testing in the drug condition was shown to be necessary to obtain this desensitization, since neither overlearning per se, nor overlearning accompanied by repeated post-session administration of scopolamine caused a reduction of sensitivity to drug.The Authors wish to acknowledge the expert assistance of Mr. Luigi AmoricoFellow (1966/1967) of the Istituto Superiore di Sanità     

Prefrontal TMS produces smaller EEG responses than motor-cortex TMS: implications for rTMS treatment in depression

Rationale The stimulus intensity of prefrontal repetitive transcranial magnetic stimulation (rTMS) during depression treatment is usually determined by adjusting it with respect to the motor threshold (MT). There is some evidence that reactivity of the prefrontal cortex to transcranial magnetic stimulation (TMS) is lower than that of the motor cortex at MT stimulation. However, it is unknown whether this is true when other stimulus intensities are used. We investigated whether the magnitude and shape of the overall TMS-evoked electroencephalographic (EEG) responses differ between prefrontal and motor cortices. Methods Magnetic pulses to the left motor and prefrontal cortices (the middle frontal gyrus identified from magnetic resonance images) were delivered at four intensities (60, 80, 100, and 120% of MT of the right abductor digiti minimi muscle) for six subjects. Simultaneously, EEG was recorded with 60 scalp electrodes. Results Global mean-field amplitudes (GMFAs) reflecting overall cortical activity were significantly smaller after prefrontal- than after motor-cortex TMS. A significant positive correlation (r _s=0.84, p<0.01) was found between GMFAs of motor- and prefrontal-cortex TMS across the experiments. However, when correlation between the responses of motor and prefrontal cortices was examined, significant positive correlations were found at 80 and 100% intensities only. Conclusions This study provides further evidence that the prefrontal and motor cortices have different reactivity to TMS, but the MT may be used for determining the stimulus intensity of prefrontal rTMS treatment in depression, at least at motor threshold intensities or near to it.     

Dynamic changes in sensitivity occur during the acute response to cocaine and methylphenidate

Rationale: We have previously shown that during the acute response to amphetamine, a stimulant that released dopamine, behavioral sensitivity to the drug undergoes dynamic changes, as evident in the altered behavioral profile expressed to the subsequent administration of a low dose of the drug. Objective: The present studies were designed to determine if these dynamic changes in sensitivity occur with amphetamine-like stimulants that act primarily by blocking dopamine uptake. Methods: Groups of animals were primed with 40 mg/kg cocaine or 30 mg/kg methylphenidate, then during the acute response, a low, locomotor-stimulant dose of amphetamine (1.5 mg/kg) was administered to probe for changes in sensitivity. Conversely, to determine whether the manifestation of the increased responsivity is idiosyncratic to amphetamine, animals were also primed with amphetamine (4 mg/kg), then probed with low doses of cocaine (10 and 20 mg/kg) or methylphenidate (10 mg/kg). Parallel microdialysis studies were performed to assess the caudate-putamen and nucleus accumbens extracellular dopamine responses. Results: Priming with the uptake blockers each resulted in a stereotypy response to the subsequent low-dose amphetamine probe. Likewise, after priming with amphetamine, the uptake blockers each induced a pronounced stereotypy response. In each case, these changes in behavioral responsivity were expressed in the absence of corresponding changes in the probe-induced regional dopamine responses. Conclusions: Dynamic changes in behavioral sensitivity during the response to acute stimulant administration are a characteristic common to both dopamine releasers and uptake blockers. These rapid changes in sensitivity may contribute to the behaviors associated with binge patterns of drug abuse. Received: 5 April 1999 / Final version: 28 May 1999     

Polymorphism of human cytochrome P450 enzymes and its clinical impact

Pharmacogenetics is the study of how interindividual variations in the DNA sequence of specific genes affect drug response. This article highlights current pharmacogenetic knowledge on important human drug-metabolizing cytochrome P450s (CYPs) to understand the large interindividual variability in drug clearance and responses in clinical practice. The human CYP superfamily contains 57 functional genes and 58 pseudogenes, with members of the 1, 2, and 3 families playing an important role in the metabolism of therapeutic drugs, other xenobiotics, and some endogenous compounds. Polymorphisms in the CYP family may have had the most impact on the fate of therapeutic drugs. CYP2D6, 2C19, and 2C9 polymorphisms account for the most frequent variations in phase I metabolism of drugs, since almost 80% of drugs in use today are metabolized by these enzymes. Approximately 5–14% of Caucasians, 0–5% Africans, and 0–1% of Asians lack CYP2D6 activity, and these individuals are known as poor metabolizers. CYP2C9 is another clinically significant enzyme that demonstrates multiple genetic variants with a potentially functional impact on the efficacy and adverse effects of drugs that are mainly eliminated by this enzyme. Studies into the CYP2C9 polymorphism have highlighted the importance of the CYP2C9*2 and *3 alleles. Extensive polymorphism also occurs in other CYP genes, such as CYP1A1, 2A6, 2A13, 2C8, 3A4, and 3A5. Since several of these CYPs (e.g., CYP1A1 and 1A2) play a role in the bioactivation of many procarcinogens, polymorphisms of these enzymes may contribute to the variable susceptibility to carcinogenesis. The distribution of the common variant alleles of CYP genes varies among different ethnic populations. Pharmacogenetics has the potential to achieve optimal quality use of medicines, and to improve the efficacy and safety of both prospective and currently available drugs. Further studies are warranted to explore the gene-dose, gene-concentration, and gene-response relationships for these important drug-metabolizing CYPs.     

The influence of genetic polymorphisms and interacting drugs on initial response to warfarin in Chinese patients with heart valve replacement

Purpose  

Compared with genetic factors, drug interactions were largely unexplored in warfarin pharmacogenetic studies. This study sought to systematically investigate the effects of genetic polymorphisms of VKORC1, STX4A, CYP2C9, CYP3A4, and GGCX and interacting drugs on the initial responses to warfarin in Chinese patients with heart valve replacement (HVR).     

Comparison of four basic models of indirect pharmacodynamic responses

Four basic models for characterizing indirect pharmacodynamic responses after drug administration have been developed and compared. The models are based on drug effects (inhibition or stimulation) on the factors controlling either the input or the dissipation of drug response. Pharmacokinetic parameters of methylprednisolone were used to generate plasma concentration and response-time profiles using computer simulations. It was found that the responses produced showed a slow onset and a slow return to baseline. The time of maximal response was dependent on the model and dose. In each case, hysteresis plots showed that drug concentrations preceded the response. When the responses were fitted with pharmacodynamic models based on distribution to a hypothetical effect compartment, the resulting parameters were dose-dependent and inferred biological implausibility. Indirect response models must be treated as distinct from conventional pharmacodynamic models which assume direct action of drugs. The assumptions, equations, and data patterns for the four basic indirect response models provide a starting point for evaluation of pharmacologie effects where the site of action precedes or follows the measured response variable.Glossary C _e Drug concentration at the hypothetical effect site - C _p Plasma concentration of drug - C _p(T_max) Plasma concentration of drug at the time of maximal response - D Dose - EC ₅₀ Drug concentration producing 50% of maximum stimulation at effect site - E _max Maximum effect attributed to drug - E _o Baseline effect prior to drug administration - IC ₅₀ Drug concentration producing 50% of maximum inhibition at effect site - K _el First-order rate constant for drug elimination - K _eo First-order rate constant for drug loss from effect site - K _in Zero-order rate constant for production of drug response - K _out First-order rate constant for loss of drug response - n Sigmoidicity factor of the sigmoid E_max equation - R Response variable - R_max Maximal (or minimal) response - R_o Initial response (time zero) prior to drug administration - t time after drug administration - T Infusion time - T_max Time to reach maximum effect following drug administration - V Volume of distribution Supported in part by Grant No. 24211 from the National Institutes of General Medical Sciences, National Institutes of Health.     

Ketamine’s antidepressant action: beyond NMDA receptor inhibition

The N-methyl-D-aspartate (NMDA) receptor antagonist ketamine is one of the most attractive antidepressants since this drug causes rapid-onset and sustained antidepressant effects in treatment resistant patients with depression. There are unanswered questions about how ketamine induces its rapid and sustained antidepressant actions. This key article suggests that (2R,6R)-HNK (hydroxynorketamine), a major metabolite of (R)-ketamine, shows antidepressant effects in rodent models of depression, indicating that the metabolism of (R)-ketamine to (2R,6R)-HNK is pivotal in its antidepressant action. Here these findings are put into context and their significance is discussed.     

Reward-Related Responses and Tonic Craving in Cocaine Addiction: An Imaging Study of the Monetary Incentive Delay Task

BackgroundCocaine addiction is associated with altered sensitivity to natural reinforcers and intense drug craving. However, previous findings on reward-related responses were mixed, and few studies have examined whether reward responses relate to tonic cocaine craving.MethodsWe combined functional magnetic resonance imaging and a monetary incentive delay task to investigate these issues. Imaging data were processed with published routines, and the results were evaluated with a corrected threshold. We compared reward responses of 50 cocaine-dependent individuals (CDs) and 45 healthy controls (HCs) for the ventral striatum (VS) and the whole brain. We also examined the regional responses in association with tonic cocaine craving, as assessed by the Cocaine Craving Questionnaire (CCQ) in CDs. We performed mediation analyses to evaluate the relationship between regional responses, CCQ score, and recent cocaine use.ResultsThe VS showed higher activation to large as compared with small or no wins, but this reward-related activity did not differ between CDs and HCs. The precentral gyrus (PCG), anterior insula, and supplementary motor area showed higher activation during large vs no wins in positive correlation with the CCQ score in CDs. Mediation analyses suggested that days of cocaine use in the prior month contributed to higher CCQ scores and, in turn, PCG reward responses.ConclusionsThe results highlight a unique relationship between reward responses of the primary motor cortex, tonic cocaine craving, and recent cocaine use. The motor cortex may partake in the cognitive motor processes critical to drug-seeking behavior in addicted individuals.     

DISADVANTAGES OF COCAINE AS A NEURONAL UPTAKE BLOCKING AGENT: COMPARISON WITH DESIPRAMINE IN GUINEA-PIG RIGHT ATRIUM

• 1 Cocaine and desipramine (DMI) are widely used as neuronal uptake blocking agents in studies of cardiac sympathetic transmission in isolated tissue preparations. It is generally assumed that these pharmacological tools do not alter transmitter release or postjunctional effector response. To test this assumption, we have compared the effects of cocaine and DMI on rate responses to sympathetic nerve stimulation and exogenous noradrenaline in guinea-pig isolated right atria.
• 2 Right atria were equilibrated with the irreversible α-adrenoreceptor antagonist benextramine to prevent any effect of presynaptic α-adrenoreceptors. Cumulative (–) noradrenaline concentration-response curves were shifted to the left by DMI (0.01–1 μM) without significant change in the resting or maximum rates. Cocaine (1–100 μM) also caused sensitisation to noradrenaline but caused a biphasic change in resting atrial rate. In addition there was a small but significant depression of the maximum rate at cocaine 10 and 100 μM.
• 3 Sympathetic nerve stimulation was achieved by applying trains of 1, 2 and 4 electrical field pulses delivered during one atrial refractory period. DMI caused a concentration dependent potentiation of responses to field stimulation. Cocaine (1 μM) caused significant enhancement of peak responses to field stimulation but no further enhancement and indeed depressed peak responses were observed at cocaine 10 and 100 μM respectively.
• 4 The time for atrial period to return halfway to baseline after field stimulation (t 1/2) was enhanced by cocaine in a concentration dependent manner as was observed with DMI. 5. We conclude that cocaine (but not DMI) decreases the maximum response to exogenous noradrenaline (postjunctional depression). The reduction of the peak response to sympathetic nerve stimulation in the presence of cocaine to below control responses suggests that cocaine also depresses the release of transmitter. These additional depressant properties of cocaine, which occur in a concentration range of neuronal uptake block, are important disadvantages and should discorage its use in experiments on sympathetic transmission.

     

Identification of dehydroxy isoquine and isotebuquine as promising antileishmanial agents

Traditional antimalarial drugs based on 4‐aminoquinolines have exhibited good antiproliferative activities against Leishmania parasites; however, their clinical use is currently limited. To identify new 4‐aminoquinolines to combat American cutaneous leishmaniasis, we carried out a full in vitro evaluation of a series of dehydroxy isoquines and isotebuquines against two Leishmania parasites such as Leishmania braziliensis and Leishmania mexicana. First, the antiproliferative activity of the quinolines was studied against the promastigote forms of L. braziliensis and L. mexicana parasites, finding that five of them exhibited good antileishmanial responses with micromolar IC₅₀ values ranging from 3.84 to 10 μM. A structure‐activity relationship analysis gave evidence that a piperidine or a morpholine attached as N‐alkyamino terminal substituent as well as the inclusion of an extra phenyl ring attached at the aniline ring of the isotebuquine core constitute important pharmacophores to generate the most active derivatives, with antileishmanial responses by far superior to those found for the reference drug, glucantime. All compounds showed a relatively low toxicity on human dermis fibroblasts, with CC₅₀ ranging from 69 to >250 μM. The five most active compounds displayed moderate to good antileishmanial activity against the intracellular amastigote form of L. braziliensis, compared to the reference drug. In particular, compound 2j was identified as the most potent agent against antimony‐resistant amastigotes of L. braziliensis with acceptable biological response and selectivity, emerging as a promising candidate for further in vivo antileishmanial evaluation. Diverse mechanism‐of‐action studies and molecular docking simulations were performed for the most active 4‐aminoquinoline.     

Effects of d,l-fenfluramine on aggressive and impulsive responding in adult males with a history of conduct disorder

Rationale: The role of serotonin in aggression and impulsivity was examined by administering the serotonin-releasing drug, d,l-fenfluramine and measuring effects on aggressive and impulsive responding under controlled laboratory conditions. Methods: Ten male subjects with a history of conduct disorder and criminal behavior participated in experimental sessions, which measured aggressive and impulsive responses. Aggression was measured using the Point subtraction Aggression paradigm (PSAP), which provides subjects with an aggressive, escape and monetary reinforced response options. Impulsive responses were measured using a paradigm which provided subjects with choices between small rewards after short delays versus larger rewards have long delays. Results: Acute challenge doses (0.2,0.4 and 0.8 mg/kg) of d,l-fenfluramine produced significant dose-dependent decreases in aggressive and impulsive responses. Escape and monetary reinforced responses were not significantly changed. Decreases in aggressive responses were therefore selective, because escape responses were not affected, and could not be attributed to a non-specific sedative action because monetary reinforced responses were slightly increased. Conclusions: Release of serotonin and/or reuptake blockade by d,l-fenfluramine is the possible mechanism for reductions in aggression and impulsivity. These results are consistent with a large body of data linking reduced serotonin function and aggressive behavior and impulsivity. Received: 5 March 1999 / Final version: 2 June 1999     

ANGIOTENSIN II- AND PHORBOL ESTER-INDUCED STEROIDOGENESIS BY OVINE ADRENOCORTICAL CELLS: EFFECT OF SEX AND THE GONADAL STATUS OF THE DONOR ANIMAL

1. Angiotensin II (Angll) is well recognized as a regulator of adrenal Cortisol production in the sheep in vivo, but studies to date have failed to reveal this action on cultured ovine adrenocortical cells. Similarly, phorbol myristate acetate (PMA), an activator of protein kinase C, also has little effect on Cortisol production from ovine adrenocortical cells in vitro. Previous studies have, however, only looked at the responses to single concentrations of Angll or PMA, but have led to the suggestion that important differences exist between adrenocortical cells of the sheep and other species. 2. We have extended previous studies by examining Cortisol production by ovine adrenocortical cells over 3h in response to a broad range of concentrations of either Angll (10^?10 to 10^?6mol/L) or PMA (10^?10 to 10^?5mol/L). In addition, we have investigated the possible role of gonadal factors in regulating these responses by comparing cultures derived from intact and gonadectomized male and female sheep. 3. Angiotensin II caused concentration-dependent increases (P<0.05) in Cortisol production in all cultures, with Cortisol production in response to Angll being greater (P < 0.05) in cultures from intact male sheep than in the cultures from orchid-ectomized males or intact females. Cortisol production in response to Angll was modest in all groups (two- to 2.6-fold increases). 4. Phorbol myristate acetate elicited a concentration-dependent inhibition (P<0.01) of basal Cortisol production in adrenocortical cultures from all groups. Phorbol myristate acetate produced a greater inhibition (P<0.05) of Cortisol production in cultures from intact male sheep than either the orchidectomized males or intact females. 5. These findings demonstrate that ovine adrenocortical cells are responsive in a concentration-dependent fashion to Angll and PMA. In addition, sex and gonadal factors may play an important role in regulating the responsiveness of adrenocortical cells to these factors.     

Fresh approaches to antidepressant drug discovery

Introduction: The success of antidepressant research has long been challenged by a limited mechanistic understanding of depression pathogenesis and antidepressant treatment response. Progress in this field has thereby consistently been hindered by a lack of novel conceptual approaches and sophisticated experimental techniques to dissect the highly intricate neurobiology of depression. Using fresh approaches to investigate the cellular and molecular mechanisms underlying depression will thus be vital for discovery of novel antidepressant targets.

Areas covered: This article provides an overview of some fundamental problems that depression research is currently facing and critically evaluates how these issues could be addressed by future research. It also discusses novel conceptual and technological advances in the field of neuroscience, particularly in regard to how they may help in providing unprecedented insight into the molecular mechanisms of depression pathogenesis.

Expert opinion: Although progress in antidepressant drug discovery has been limited over recent years, modern innovations in neuroscience, molecular biology, genetics and bioinformatics are just beginning to revolutionize depression research and to reveal novel and promising treatment targets. Integrating findings from a range of relevant experimental models and using the most advanced technology will be vital for the future success of antidepressant drug discovery.     

Beneficial acute antidepressant effects of aripiprazole as an adjunctive treatment or monotherapy in bipolar patients unresponsive to mood stabilizers: results from a 16-week open-label trial

Objective: Several lines of research suggested that aripiprazole might be a useful treatment for acute bipolar depression. The aim of this open-label trial is to give more evidence of the clinical effectiveness and tolerability of aripiprazole in acute bipolar depression. Research design and methods: Aripiprazole response was prospectively assessed for 16 weeks using the Montgomery-Asberg Depression Rating Scale (MADRS), the Clinical Global Impression Severity Scale (CGI-S), and the Young Mania Rating Scale in 85 bipolar patients with acute depression inadequately responsive to one mood stabilizer. Main outcome measures: Aripiprazole was well tolerated. Only three (3.5%) patients discontinued the study for side effects. The most common side effect was akathisia, occurring in 17/80 (21.2%) patients. Patients showed statistically insignificant weight gain (0.9 ± 2.64 kg) over the 16-week trial. Results: Patients showed a significant decrease in mean MADRS and CGI-S, and 80 (94.1%) patients completed the 16-week trial. Thirty-nine (45.8%) patients received aripiprazole as monotherapy and 46 received the drug adjunctively (54.1%). Fifty-two (65%) patients met criteria for response (≥ 50% reduction in MADRS total score), 30 (37.5%) patients met criteria for remission (final MADRS total score ≤ 12). Conclusions: Aripiprazole was associated with beneficial effects on mood in patients with bipolar depression, and appears well tolerated with very small changes in mean body weight. These results highlight the potential benefits of aripiprazole for bipolar disorder patients. However, double-blind, placebo-controlled studies are necessary to confirm aripiprazole's efficacy, tolerability and safety in bipolar depression.     

Heterogeneity in the Co-occurrence of Substance Use and Posttraumatic Stress Disorder: A Latent Class Analysis Approach

Objective: Posttraumatic stress disorder (PTSD) often co-occurs with substance use (SU). Although there has been independent research on subgroups of participants based on their PTSD or SU responses, rarely are PTSD-SU typologies examined consistent with a precision medicine approach (and corresponding person-centered statistical approaches). The current study examined the nature and construct validity (covariates of depression, physical aggression, verbal aggression, anger, hostility, reckless and self-destructive behaviors [RSDB]) of the best-fitting latent class solution in categorizing participants based on PTSD (PTSD Checklist for DSM-5) and alcohol/drug use responses (Alcohol Use and Disorders Identification Test Alcohol Consumption Questions, Drug Abuse Screening Test). Methods: The sample included 375 trauma-exposed participants recruited from Amazon’s Mechanical Turk online labor market. Results: Latent class analyses indicated an optimal three-class solution (low PTSD/SU, moderate PTSD/drug and high alcohol, and high PTSD/SU). Multinomial logistic regressions indicated that depression (OR?=?1.22) and frequency of RSDBs (OR?=?1.20) were significant predictors of the moderate PTSD/drug and high alcohol class versus the low PTSD/SU class. Depression (OR?=?1.55) and frequency of RSDBs (OR?=?1.19) were significant predictors of the high PTSD/SU class versus the low PTSD/SU class. Only depression (OR?=?1.27) was a significant predictor of the high PTSD/SU class versus the moderate PTSD/drug and high alcohol class. Conclusions: Results provide construct validity support for three meaningful latent classes with unique relations with depression and RSDBs. These findings improve our understanding of heterogeneous PTSD-SU comorbidity patterns and highlight acknowledgment of such subtyping (subgrouping) in considering differential treatment options, treatment effectiveness, and resource allocation.     

Genetic Risk For Nicotine Dependence in the Cholinergic System and Activation of the Brain Reward System in Healthy Adolescents

Genetic variation in a genomic region on chromosome 15q25.1, which encodes the alpha5, alpha3, and beta4 subunits of the cholinergic nicotinic receptor genes, confers risk to smoking and nicotine dependence (ND). Neural reward-related responses have previously been identified as important factors in the development of drug dependence involving ND. Applying an imaging genetics approach in two cohorts (N=487; N=478) of healthy non-smoking adolescents, we aimed to elucidate the impact of genome-wide significant smoking-associated variants in the CHRNA5–CHRNA3–CHRNB4 gene cluster on reward-related neural responses in central regions such as the striatum, orbitofrontal and anterior cingulate cortex (ACC), and personality traits related to addiction. In both samples, carriers of the rs578776 GG compared with AG/AA genotype showed a significantly lower neural response to reward outcomes in the right ventral and dorsal ACC but not the striatum or the orbitofrontal cortex. Rs578776 was unrelated to neural reward anticipation or reward magnitude. Significantly higher scores of anxiety sensitivity in GG compared with AG/AA carriers were found only in sample 1. Associations with other personality traits were not observed. Our findings suggest that the rs578776 risk variant influences susceptibility to ND by dampening the response of the ACC to reward feedback, without recruiting the striatum or orbitofrontal cortex during feedback or anticipation. Thus, it seems to have a major role in the processing of and behavioral adaptation to changing reward outcomes.     

Applications of Fourier transform infrared spectroscopic imaging to tablet dissolution and drug release

Introduction: Solid oral dosage forms are the most commonly used method for administering active pharmaceutical ingredients to patients. Understanding the mechanisms and processes of drug release is essential for improving the design of pharmaceutical tablets.

Areas covered: In this review, recent approaches where attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopic imaging has been applied to study tablet dissolution and drug release have been investigated. Drug release studies of model pharmaceutical systems composed of drug/polymer mixtures in the presence of aqueous solutions have been discussed, as has the subsequent combination with UV/Vis spectroscopic detection to quantify the amount of drug dissolved as a function of time. The use of a single-reflection ATR accessory with a diamond crystal allows for in situ FTIR imaging of tablet compaction and dissolution.

Expert opinion: ATR-FTIR imaging can address the challenges of investigating the mechanisms of drug release from a range of innovative new delivery systems. Unlike standard dissolution tests, this spectroscopic imaging method obtains insight and information about changes within the tablet during dissolution. Areas where ATR-FTIR imaging has shown further potential to be particularly useful are for the study of multi-layered solid tablets, high-throughput analysis, use of microfluidic devices and for surface-enhanced ATR-FTIR spectroscopy.