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OBJECTIVE: To investigate whether variable antidepressant response may be influenced by an interaction between the serotonin transporter promoter polymorphism (5-HTTLPR) and antidepressant concentration. METHODS: Elderly subjects with depression treated with paroxetine (n = 110) were genotyped and assessed with the Hamilton Rating Scale for Depression (HAMD). A mixed-effect analysis of repeated measures was used. RESULTS: There was an interaction between early paroxetine concentration and 5-HTTLPR genotype on symptomatic improvement over 12 weeks (F(18,59.5) = 1.8, p < 0.05), as well as main effects of both paroxetine concentration (F(68,55.3) = 2.4, p < 0.005) and genotype (F(2,74.2) = 5.7, p < 0.005). Paroxetine concentrations were correlated with change in HAMD scores after 2 weeks of treatment in subjects with the short (s) allele (r = 0.31, p < 0.05) but not in subjects homozygous for the long (l) allele. CONCLUSION: The results demonstrate a concentration-response relation for paroxetine in late-life depression and support the hypothesis for both a direct main effect and a moderating influence of 5-HTTLPR alleles on this concentration-response relation. [ABSTRACT FROM AUTHOR]

The elderly frequently have changes in pharmacokinetics, sensitivity to medications, homeostatic reserve (ability to tolerate physiological challenges), exposure to multiple medications, and adherence. All of these age-associated factors can potentially influence total exposure to medication, adverse effects, and subsequent treatment outcome. Most clinical trials are performed with healthy, younger adults. Extrapolating the results of these trials to the elderly may be inappropriate, particularly for the antidepressant treatment of depression. The authors review these age-associated differences and discuss their implications for antidepressant use in older adults. [ABSTRACT FROM AUTHOR]

The objective of this study was to evaluate whether the disposition of the selective serotonin reuptake inhibitor, citalopram, could be robustly captured using 1 to 2 concentration samples per subject in 106 patients participating in 2 clinical trials. Nonlinear mixed-effects modeling was used to evaluate the pharmacokinetic parameters describing citalopram's disposition. Both a prior established 2-compartment model and a de novo 1-compartment pharmacokinetic model were used. Covariates assessed were concomitant medications, race, sex, age (22-93 years), and weight. Covariates affecting disposition were assessed separately and then combined in a stepwise manner. Pharmacokinetic characteristics of citalopram were well captured using this sparse sampling design. Two covariates (age and weight) had a significant effect on the clearance and volume of distribution in both the 1- and 2-compartment pharmacokinetic models. Clearance decreased 0.23 L/h for every year of age and increased 0.14 L/h per kilogram body weight. It was concluded that hyper-sparse sampling designs are adequate to support population pharmacokinetic analysis in clinically treated populations. This is particularly valuable for populations such as the elderly, who are not typically available for pharmacokinetic studies. [ABSTRACT FROM AUTHOR]

Objective: Several immunological biomarkers are altered in late-life major depressive disorder (LLD). Immunological alterations could contribute to LLD's consequences, but little is known about the relations between specific immunological biomarkers and brain health in LLD. We performed an exploratory pilot study to identify, from several candidates, the specific immunological biomarkers related to important aspects of brain health that are altered in LLD (brain structure and executive function)., Methods: Adults (n = 31) were at least 60 years old and had major depressive disorder. A multiplex immunoassay assessed 13 immunological biomarkers, and we examined their associations with structural MRI (grey matter volume and white matter hyperintensity volume (WMH)) and executive function (Color-Word Interference and Trail-Making tests) measures., Results: Vascular endothelial growth factor (VEGF) and the chemokine eotaxin had significant negative associations with grey matter volume (VEGF: n = 31, r = -0.65; eotaxin: n = 29, r = -0.44). Tumor necrosis factor alpha (TNF-α) had a significant positive relationship with WMHs (n = 30, r = 0.52); interferon-γ (IFN-γ) and macrophage inflammatory protein-1α (MIP-1α) were also significantly associated with WMHs (IFN-γ: n = 31, r = 0.48; MIP-1α: n = 29, r = 0.45). Only eotaxin was associated with executive function (set-shifting performance as measured with the Trail-making test: n = 33, r = -0.43)., Conclusions: Immunological markers are associated with brain structure in LLD. We found the immunological correlates of grey and white matter differ. Prospective studies are needed to evaluate whether these immunological correlates of brain health increase the risk of LLD's consequences. Eotaxin, which correlated with both grey matter volume and set-shifting performance, may be particularly relevant to neurodegeneration and cognition in LLD. Copyright © 2016 John Wiley & Sons, Ltd., (Copyright © 2016 John Wiley & Sons, Ltd.)

Personalizing treatment for late-life depression requires identifying and integrating information from multiple factors that influence treatment efficacy (moderators). We performed exploratory moderator analyses using data from a multi-site, randomized, placebo-controlled, double-blind trial of aripiprazole augmentation. Patients (n = 159) aged ≥60 years had major depressive disorder that failed to remit with venlafaxine monotherapy. We examined effect sizes of 39 potential moderators of aripiprazole (vs. placebo) augmentation efficacy using the outcome of percentage reduction in depressive symptom after 12 weeks. We then incorporated information from the individually relevant variables in combined moderators. A larger aripiprazole treatment effect was related to: white race, better physical function, better performance on Trail-Making, attention, immediate, and delayed memory tests, greater psychomotor agitation and suicidality symptoms, and a history of adequate antidepressant pharmacotherapy. A smaller aripiprazole treatment effect was observed in patients with: more pain and more work/activity impairment and libido symptoms. Combining information from race and Trail-Making test performance (base combined moderator (Mb*)) produced a larger effect size (Spearman effect size = 0.29 (95% confidence interval (CI): 0.15, 0.42)) than any individual moderator. Adding other individually relevant moderators in the full combined moderator (Mf*) further improved effect size (Spearman effect size = 0.39 (95% CI: 0.25, 0.52)) and identified a sub-group benefiting more from placebo plus continuation venlafaxine monotherapy than adjunctive aripiprazole. Combining moderators can help clinicians personalize depression treatment. We found the majority of our patients benefited from adjunctive aripiprazole, but a smaller subgroup that is identifiable using clinical measures appeared to benefit more from continuation venlafaxine plus placebo., Competing Interests: SFS, MLW, BSD, MAB, MAD, SJA, FEL have no conflicts of interest to declare. Dr. Lenze reports current grants from NIH (NIA, NCCIH, NIMH, OBSSR), grants from FDA, grants from McKnight Brain Research Foundation, grants from Taylor Family Institute for Innovative Psychiatric Research, grants from Barnes Jewish Foundation, grants from Takeda, grants from Lundbeck, and past grants from Roche, Sidney R. Baer Foundation, that did not influence the submitted work. Dr. Reynolds III, MD reports grants from National Institute of Health (NIH), grants from Center for Medicare and Medicaid Services (CMS), grants from Patient Centered Outcomes Research Institute (PCORI), grants from John A. Hartford Foundation, grants from American Foundation for Suicide Prevention, grants from Commonwealth of Pennsylvania, grants from Clinical and Translational Science Institute (CTSI), grants from National Palliative Care Research Center (NPCRC), during the conduct of the study; personal fees from American Association for Geriatric Psychiatry, personal fees from UPMC Endowment in Geriatric Psychiatry, an speakers honorarium from Medscape/WebMD did not influence the submitted work; in addition, Dr. Reynolds III, MD has a patent Psychometric analysis of the Pittsburgh Sleep Quality Index (PSQI) with royalties paid to Dr. Daniel Buysse. Bristol Meyers Squibb, Forrest Labs, Lily, Pfizer provide pharmaceutical supplies for NIH-sponsored work (these pharmaceutical companies play no role in the design, analysis, or reporting of my data in peer reviewed journals). Dr. Blumberger reports other from Tonika Magventure, grants from Canadian Institutes of Health Research, grants from National Institute of Health, other from Brain Research and Development Services, grants from Brain Canada, did not influence the submitted work. Dr. Mulsant reports grants from National Institute of Mental Health (NIMH, USA), non-financial support from Pfizer, non-financial support from Bristol-Myers-Squibb, during the conduct of the study; grants from Brain Canada, grants from Canadian Institutes of Health Research, grants from US National Institute of Health, grants from Centre for Addiction and Mental Health Foundation, non-financial support from Eli Lilly, non-financial support from General Electric, did not influence the submitted work. Dr. Karp reports receipt of medication supplies for investigator initiated studies from Pfizer and Invidior that did not influence the submitted work., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Although potentially modifiable risk factors for interferon-alpha (IFN-α)-associated depression (IFN-MDD) have been identified, it is not currently known how they interact to confer risk. In the present study we prospectively investigated interactions among poor sleep quality, high-stress, pre-existing depressive symptoms, and polyunsaturated fatty acid status. Non-depressed hepatitis C patients (n=104) were followed prospectively during IFN-α therapy. IFN-MDD occurs in 20-40% of patients and was diagnosed using the Structured Clinical Interview of DSM-IV (SCID-IV), with incidence examined using Cox regression. Baseline Pittsburgh Sleep Quality Inventory (PSQI), Perceived Stress Scale (PSS), Beck Depression Inventory (BDI), and a range of plasma long-chain fatty acid levels were measured (gas chromatography) - focusing on the ratio of arachidonic acid (AA) to docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) (AA/EPA+DHA). The AA/EPA+DHA ratio (Β=0.40 ± 0.16; p=0.006), PSQI (Β=0.12 ± 0.04; p=0.001), PSS (Β=0.07 ± 0.02; p<0.001), and baseline BDI (Β=0.05 ± 0.02; p<0.001) each individually predicted IFN-MDD incidence. In step-wise Cox regression eliminating non-significant variables, two interactions remained significantly predictive: PSQI*AA/EPA+DHA (p=0.008) and PSS*AA/EPA+DHA (p=0.01). Receiver Operator Curves (ROC) were used to examine the specificity and sensitivity of IFN-MDD prediction. When sleep was normal (PSQI<5), AA/EPA+DHA was strongly predictive of IFN-MDD (AUC=91 ± 6; p=0.002). For example, among those with AA/EPA+DHA less than the median (4.15), none with PSQI<5 developed depression. Conversely, neither PSS nor PSQI was statistically associated with depression risk in those with an elevated AA/EPA+DHA ratio. These data demonstrate that the AA/EPA+DHA ratio moderates the effect of poor sleep on risk for developing IFN-MDD and may have broader implications for predicting and preventing MDD associated with inflammation., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Importance: More than 50% of older adults with late-life major depressive disorder fail to respond to initial treatment with first-line pharmacological therapy., Objectives: To assess typical patterns of response to an open-label trial of extended-release venlafaxine hydrochloride (venlafaxine XR) for late-life depression and to evaluate which clinical factors are associated with the identified longitudinal response patterns., Design, Setting, and Participants: Group-based trajectory modeling was applied to data from a 12-week open-label pharmacological trial conducted in specialty care as part of the Incomplete Response in Late Life: Getting to Remission Study. Clinical prognostic factors, including domain-specific cognitive performance and individual depression symptoms, were examined in relation to response trajectories. Participants included 453 adults aged 60 years or older with current major depressive disorder. The study was conducted between August 2009 and August 2014., Intervention: Open-label venlafaxine XR (titrated up to 300 mg/d) for 12 weeks., Main Outcomes and Measures: Subgroups exhibiting similar response patterns were derived from repeated measures of overall depression severity obtained using the Montgomery-Asberg Depression Rating Scale., Results: Among the 453 study participants, 3 subgroups with differing baseline depression severity clearly responded to treatment: one group with the lowest baseline severity had a rapid response (n = 69 [15.23%]), and distinct responses were also apparent among groups starting at moderate (n = 108 [23.84%]) and higher (n = 25 [5.52%]) baseline symptom levels. Three subgroups had nonresponding trajectories: 2 with high baseline symptom levels (totaling 35.98%: high, nonresponse 1, n = 110 [24.28%]; high, nonresponse 2, n = 53 [11.70%]) and 1 with moderate baseline symptom levels (n = 88 [19.43%]). Several factors were independently associated with having a nonresponsive trajectory, including greater baseline depression severity, longer episode duration, less subjective sleep loss, more guilt, and more work/activity impairment (P < .05). Higher delayed memory (list recognition) performance was independently associated with having a rapid response (adjusted odds ratio = 2.22; 95% CI, 1.18-4.20)., Conclusions and Relevance: Based on the observed trajectory patterns, patients who have late-life depression with high baseline depression severity are unlikely to respond after 12 weeks of treatment with venlafaxine XR. However, high baseline depression severity alone may be neither a necessary nor sufficient predictor of treatment nonresponse., Trial Registration: clinicaltrials.gov Identifier: NCT00892047.

Objective: Some patients with hepatitis C starting interferon-α (IFN-α) therapy experience depression, although many patients do not develop depressive symptoms. We have found that poor sleep is associated with increased depressive symptoms on average. It is unknown whether this association holds generally or is driven by a specific, distinct subgroup. This investigation first determined whether patterns of change in depressive symptoms form clinically meaningful, distinct subgroups and then tested the extent to which sleep disturbances are associated with a less favorable depression trajectory., Method: Group-based trajectory modeling was used on 124 patients with hepatitis C who started IFN-α therapy. The Pittsburgh Sleep Quality Index (PSQI) assessed pretreatment sleep, the Beck Depression Inventory minus the sleep question assessed depression over time, and the Structured Clinical Interview for DSM-IV provided categorical diagnoses., Results: Three distinct subgroups were found, where each subgroup shared similar patterns of depressive symptoms over time. The groups were characterized as "nondepressed," "slow increase," and "rapid increase." The nondepressed subgroup (44.4%) experienced low depressive symptoms with little change over time. In comparison, all rapid increasers (11.3%) were diagnosed as having a mood disorder by 12 weeks of treatment. The PSQI was strongly associated with group membership, where the odds of developing a rapid increase was elevated 39% for every unit-score increase in the PSQI compared with individuals who remained nondepressed (odds ratio = 1.39, 95% confidence interval = 1.07-1.80, adjusted for depression at baseline)., Conclusions: Only a distinct subpopulation of people is notably vulnerable to a developing a rapid increase in depression symptoms during IFN-α therapy. This group may be identifiable by their markedly poor sleep before IFN-α therapy.

Inflammatory cytokines can sometimes trigger depression in humans, are often associated with depression, and can elicit some behaviors in animals that are homologous to major depression. Moreover, these cytokines can affect monoaminergic and glutamatergic systems, supporting an overlapping pathoetiology with major depression. This suggests that there could be a specific major depression subtype, inflammatory cytokine-associated depression (ICAD), which may require different therapeutic approaches. However, most people do not develop depression, even when exposed to sustained elevations in inflammatory cytokines. Thus several vulnerabilities and sources of resilience to inflammation-associated depression have been identified. These range from genetic differences in neurotrophic and serotonergic systems to sleep quality and omega-3 fatty acid levels. Replicating these sources of resilience as treatments could be one approach for preventing "ICAD". This article is part of a Special Issue entitled SI: Neuroimmunology in Health And Disease., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background & Aims: Cirrhosis is associated with significant pain and disability, the etiologies of which are poorly understood. We investigated whether the pain and disability in patients with cirrhosis are associated with systemic inflammation and psychiatric symptoms., Methods: In a prospective study, we recruited 193 patients with cirrhosis caused by hepatitis C virus infection, nonalcoholic steatohepatitis, or alcohol from the hepatology clinic at the University of Pittsburgh. Patients were assessed using the McGill Pain Questionnaire, the Hospital Anxiety and Depression Scale, the Pittsburgh Sleep Quality Index, and the Pain Disability Index. Serum samples were collected and markers of inflammation were measured using standardized Luminex assays (Milipore, St. Charles, MO). We evaluated factors associated with pain, pain-related disability, and chronic opioid use by using multivariable regression models., Results: Pain was reported by 79% of patients, pain-related disability was reported by 75%, and depression and/or anxiety was reported by 47%; the average Model for End-Stage Liver Disease score was 12 ± 5. Serum samples from 58% percent of patients had increased levels of C-reactive protein. Opioids were prescribed for 30% of patients with pain. In multivariate analysis, factors significantly associated with pain included younger age (odds ratio [OR]/y, 0.93; 95% confidence interval [CI], 0.90-0.99), serum level of interleukin 6 (OR per pg/L, 1.63; 95% CI, 1.09-2.58), Hospital Anxiety and Depression Scale score (OR/point, 1.14; 95% CI, 1.07-1.24), and etiology (hepatitis C virus infection vs alcohol: OR, 3.70; 95% CI, 1.27-11.11). Disability scores were related significantly to psychiatric symptoms (incidence rate ratio [IRR]/point, 1.04; 95% CI, 1.02-1.05), prescription opioid use (IRR, 1.49; 95% CI, 1.14-1.94), Model for End-Stage Liver Disease score (IRR/point, 1.02; 95% CI, 1.0001-1.05), level of C-reactive protein (IRR per mg/dL, 1.13; 95% CI, 1.02-1.24), and pain severity (IRR/point, 1.19; 95% CI, 1.08-1.32)., Conclusions: Pain and disability are common among patients with cirrhosis, and are associated with inflammation, psychiatric symptoms, and opioid use, which potentially are modifiable. Although opioids are used commonly to treat pain, psychiatric symptoms and inflammation also might be treatment targets in this population., (Published by Elsevier Inc.)

Objective: Although poor sleep accompanies depression, it is unknown which specific sleep abnormalities precede depression. This is similarly the case for depression developing during interferon-α (IFN-α) therapy. Because vulnerability becomes evident in those who slept poorly before IFN-α, we prospectively determined which specific aspect of sleep could predict subsequent depression., Methods: Two nights of polysomnography with quantitative electroencephalogram (EEG) were obtained in 24 adult, euthymic subjects--all subsequently treated with IFN-α for hepatitis C. Every 2 weeks, a Beck Depression Inventory-II (BDI-II) score was obtained, and the maximal increase in BDI-II from pre-treatment baseline--excluding the sleep question--was determined., Results: The delta sleep ratio (DSR; an index of early-night restorative delta power) was inversely associated with BDI-II increases (p<0.01), as was elevated alpha power (8-12 Hz; p<0.001). Both delta (0.5-4 Hz) and alpha power exhibited high between-night correlations (r=0.83 and 0.92, respectively). In mixed-effect repeated-measure analyses, there was an interaction between alpha power and DSR (p<0.001)--subjects with low alpha power and elevated DSR were resilient to developing depression. Most other sleep parameters--including total sleep time and percentage of time in slow wave sleep--were not associated with subsequent changes in depression., Conclusions: Both high DSR and low alpha power may be specific indices of resilience. As most other aspects of sleep were not associated with resilience or vulnerability, sleep interventions to prevent depression may need to specifically target these specific sleep parameters.

Objective: Antidepressant side effects are a significant public health issue, associated with poor adherence, premature treatment discontinuation, and, rarely, significant harm. Older adults assume the largest and most serious burden of medication side effects. We investigated the association between antidepressant side effects and genetic variation in the serotonin system in anxious, older adults participating in a randomized, placebo-controlled trial of the selective serotonin reuptake inhibitor (SSRI) escitalopram., Methods: Adults (N = 177) aged ≥ 60 years were randomized to active treatment or placebo for 12 weeks. Side effects were assessed using the Udvalg fur Kliniske Undersøgelser side-effect rating scale. Genetic polymorphisms were putative functional variants in the promoters of the serotonin transporter and 1A and 2A receptors (5-HTTLPR [L/S + rs25531], HTR1A rs6295, HTR2A rs6311, respectively)., Results: Four significant drug-placebo side-effect differences were found: increased duration of sleep, dry mouth, diarrhea, and diminished sexual desire. Analyses using putative high- versus low-transcription genotype groupings revealed six pharmacogenetic effects: greater dry mouth and decreased sexual desire for the low- and high-expressing serotonin transporter genotypes, respectively, and greater diarrhea with the 1A receptor low-transcription genotype. Diminished sexual desire was experienced significantly more by high-expressing genotypes in the serotonin transporter, 1A, or 2A receptors. There was not a significant relationship between drug concentration and side effects nor a mean difference in drug concentration between low- and high-expressing genotypes., Conclusion: Genetic variation in the serotonin system may predict who develops common SSRI side effects and why. More work is needed to further characterize this genetic modulation and to translate research findings into strategies useful for more personalized patient care., (Published by Elsevier Inc.)

Objective: Cognitive impairments are a feature of bipolar disorder (BD) and could be worsened by inflammatory cytokines. We determined whether (i) serum interleukin-1 receptor antagonist (IL-1RA) was increased in elderly BD subjects; (ii) whether IL-1RA was associated with worse neurocognitive function; and (iii) whether IL-1RA was associated with white matter integrity., Methods: Twenty-one euthymic BD patients (65 +/- 9 years) with serum available for IL-1RA measures by enzyme-linked immunoassays were compared with 26 similarly aged control participants. Four factor analysis-derived z-scores and a global z-score were obtained from a battery of 21 neurocognitive tests. Diffusion tensor images were used to obtain fractional anisotropy (FA), and an automated labeling pathway algorithm was used to obtain white matter hyperintensity burden., Results: Interleukin-1 receptor antagonist was elevated in BD subjects compared with controls (439+/-326 pg/mL vs. 269+/-109 pg/mL; p = 0.004). Moreover, IL-1RA was inversely correlated with three cognitive function factors and global cognition (r = -0.37; p = 0.01). IL-1RA continued to correlate with global cognitive function even when covarying for either IL-6 or brain-derived neurotrophic factor. Although FA was lower in BD subjects (0.368 +/- 0.02 vs. 0.381 +/- 0.01; p = 0.02), IL-1RA was not associated with FA or white matter hyperintensity burden., Conclusion: Elevated serum levels of IL-1RA in BD subjects, even during euthymic states, were associated with worse cognitive function. This association was not explained by co-occurring increases in IL-6, by decreased brain-derived neurotrophic factor, nor by measures of white matter integrity. These cross-sectional findings support the possibility that the IL-1 family may contribute to cognitive impairments in BD., (Copyright © 2013 John Wiley & Sons, Ltd.)

Depression is a leading cause of disease burden, disability and distress for millions of older adults. Thus, prevention of late-life depression is a priority research area. This article addresses the science of late-life depression prevention with the following: 1) an introduction to the Institute of Medicine framework of universal, selective and indicated prevention as it pertains to late-life depression, with particular attention to successes of indicated and selective prevention in primary care; 2) a discussion of how biomarkers can be integrated into prevention research, using interferon-alpha-induced depression as a model; 3) an outline for expansion of prevention to non-specialist care delivery systems in Low and Middle Income Countries - thus, extending the reach of current successful approaches; 4) a description of a novel approach to simultaneous testing of universal, selective and indicated prevention in late-life depression, with emphasis on study design features required to achieve practical, scalable tests of health impact.

Objective: Anger worsens in some patients during interferon-alpha (IFN-α) therapy. Elevated anger has also been associated with lower long-chain omega-3 (LCn-3) fatty acid levels. We examined whether fatty acids could influence vulnerability to anger during IFN-α exposure., Methods: Plasma arachidonic acid (AA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) levels were determined prior to IFN-α therapy by mass spectroscopy. Repeated-measure analyses examined the relationship between AA/EPA+DHA and the subsequent development of labile anger and irritability in 82 subjects who prospectively completed the Anger, Irritability, and Assault Questionnaire (AIAQ) during the first eight weeks of IFN-α therapy., Results: Prior to IFN-α therapy, AA/EPA+DHA did not correlate with either labile anger or irritability. Pre-treatment AA/EPA+DHA did correlate with the subsequent maximal increase in labile anger during IFN-α therapy (r=0.33; p=0.005). Over time, labile anger increased more in subjects with above median AA/EPA+DHA ratios (p<0.05). Of the 17 subjects ultimately requiring psychiatric intervention for anger, 14/17 had above-median AA/EPA+DHA ratios (p=0.009). There was also an interaction with the tumor necrosis factor-alpha (TNF-α) promoter polymorphism (A-308G), such that only those with both elevated AA/EPA+DHA and the A allele had increased labile anger (p=0.001). In an additional 18 subjects, we conversely observed that selective serotonin reuptake inhibitor treatment was associated with increased irritability during IFN-α therapy., Conclusion: LCn-3 fatty acid status may influence anger development during exposure to elevated inflammatory cytokines, and may interact with genetic risk for increased brain TNF-α. LCn-3 supplements may be one strategy for minimizing this adverse side effect of IFN-α., (© 2013.)

Mounting evidence indicates that inflammatory cytokines contribute to the development of depression in both medically ill and medically healthy individuals. Cytokines are important for development and normal brain function, and have the ability to influence neurocircuitry and neurotransmitter systems to produce behavioral alterations. Acutely, inflammatory cytokine administration or activation of the innate immune system produces adaptive behavioral responses that promote conservation of energy to combat infection or recovery from injury. However, chronic exposure to elevated inflammatory cytokines and persistent alterations in neurotransmitter systems can lead to neuropsychiatric disorders and depression. Mechanisms of cytokine behavioral effects involve activation of inflammatory signaling pathways in the brain that results in changes in monoamine, glutamate, and neuropeptide systems, and decreases in growth factors, such as brain-derived neurotrophic factor. Furthermore, inflammatory cytokines may serve as mediators of both environmental (e.g. childhood trauma, obesity, stress, and poor sleep) and genetic (functional gene polymorphisms) factors that contribute to depression's development. This review explores the idea that specific gene polymorphisms and neurotransmitter systems can confer protection from or vulnerability to specific symptom dimensions of cytokine-related depression. Additionally, potential therapeutic strategies that target inflammatory cytokine signaling or the consequences of cytokines on neurotransmitter systems in the brain to prevent or reverse cytokine effects on behavior are discussed., (Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.)

Cross-sectional studies have found that an elevated ratio of arachidonic acid to omega-3 fatty acid is associated with depression, and controlled intervention studies have found that decreasing this ratio through administration of omega-3 fatty acids can alleviate depressive symptoms. Additionally, arachidonic acid and omega-3 fatty acids have opposing effects on inflammatory signaling. Exogenous administration of the inflammatory cytokine interferon-alpha (IFN-α) can trigger a depressive episode in a subset of vulnerable people, though associated risk factors remain poorly understood. Using a within-subject prospective design of 138 subjects, we examined whether baseline long-chain omega-3 (docosahexaenoic acid - DHA; eicosapentaenoic acid - EPA) and omega-6 (arachidonic acid - AA; di-homo-gamma-linolenic acid - DGLA) fatty acid status was associated with depression vulnerability in hepatitis C patients treated with IFN-α. Based on the literature, we had specific a priori interest in the AA/EPA+DHA ratio. Lower baseline DHA predicted depression incidence (p=0.04), as did elevated DGLA (p=0.02) and an elevated AA/EPA+DHA ratio (p=0.007). The AA/EPA+DHA ratio predicted depression even when controlling for other critical variables such as sleep quality and race. A higher AA/EPA+DHA ratio was positively associated with both increasing Montgomery-Asperg Depression Rating Scores over time (F=4.0; p<0.05) as well as interleukin-6 levels (F=107.4; p<0.05) but not C-reactive protein. Importantly, omega-3 and omega-6 fatty acid status was not associated with sustained viral response to IFN-α treatment. These prospective data support the role of fatty acid status in depression vulnerability and indicate a potential role for omega-3 fatty acids in the prevention of inflammation-induced depression., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Depression has been associated with inflammation, and inflammation may both influence and interact with growth factors such as brain-derived neurotrophic factor (BDNF). Both the functional Val66Met BDNF polymorphism (rs6265) and BDNF levels have been associated with depression. It is thus plausible that decreased BDNF could mediate and/or moderate cytokine-induced depression. We therefore prospectively employed the Beck Depression Inventory-II (BDI-II), the Hospital Anxiety and Depression Scale (HADS), and the Montgomery-Asberg Depression Rating Scale (MADRS) in 124 initially euthymic patients during treatment with interferon-alpha (IFN-α), assessing serum BDNF and rs6265. Using mixed-effect repeated measures, lower pretreatment BDNF was associated with higher depression symptoms during IFN-α treatment (F144,17.2=6.8; P<0.0001). However, although the Met allele was associated with lower BDNF levels (F1,83.0=5.0; P=0.03), it was only associated with increased MADRS scores (F4,8.9=20.3; P<0.001), and not the BDI-II or HADS. An exploratory comparison of individual BDI-II items indicated that the Met allele was associated with suicidal ideation, sadness, and worthlessness, but not neurovegetative symptoms. Conversely, the serotonin transporter promoter polymorphism (5-HTTLPR) short allele was associated with neurovegetative symptoms such as insomnia, poor appetite and fatigue, but not sadness, worthlessness, or suicidal ideation. IFN-α therapy further lowered BDNF serum levels (F4,37.7=5.0; P=0.003), but this decrease occurred regardless of depression development. The findings thus do not support the hypothesis that decreasing BDNF is the primary pathway by which IFN-α worsens depression. Nonetheless, the results support the hypothesis that BDNF levels influence resiliency against developing inflammatory cytokine-associated depression, and specifically to a subset of symptoms distinct from those influenced by 5-HTTLPR.

Older adults are among the most vulnerable to adverse cognitive effects of psychotropic medications and, therefore, the personalization of psychotropic treatment based on adverse drug reactions in this demographic is of great importance. We examined changes on neuropsychological tests of attention attributable to selective serotonin reuptake inhibitor (SSRI) treatment in anxious older adults. We also examined whether variation in serotonin receptor genes was associated with reduced attentional performance with SSRIs. We examined change from pre- to post-treatment in two attention measures - digit span and coding - in 133 adults aged ≥60 yr with generalized anxiety disorder in a 12-wk trial of escitalopram vs. placebo. We also examined attentional change in relation to genetic variability in four central serotonin receptors: the serotonin transporter and serotonin 1A, 2A and 1B receptors. Digit span scores were significantly lowered in patients receiving escitalopram relative to placebo, indicating reduced attentional performance attributable to the SSRI. Individuals with high-transcription variants in the receptors 5-HTR2A rs6311 and 5-HTR1B rs11568817 had greater reductions in attention with SSRI treatment compared to placebo. We conclude that SSRIs reduce attention in older adults, particularly in those with high-expression genetic variants at the serotonin 2A and 1B receptors. Analysing neuropsychological changes with SSRIs in relation to genetic variation in the serotonin system may be a useful strategy for detecting subgroups of older adults who are more susceptible to side-effects of SSRIs. These results, if confirmed, could lead to the personalization of SSRI use to reduce adverse neurocognitive effects.

Converging translational evidence has implicated elevated immune-inflammatory signaling activity in the pathoetiology of mood disorders, including major depressive disorder and bipolar disorder. This is supported in part by cross-sectional evidence for increased levels of proinflammatory eicosanoids, cytokines and acute-phase proteins during mood episodes, and prospective longitudinal evidence for the emergence of mood symptoms in response to chronic immune-inflammatory activation. In addition, mood-stabilizer and atypical antipsychotic medications downregulate initial components of the immune-inflammatory signaling pathway, and adjunctive treatment with anti-inflammatory agents augment the therapeutic efficacy of antidepressant, mood stabilizer and atypical antipsychotic medications. Potential pathogenic mechanisms linked with elevated immune-inflammatory signaling include perturbations in central serotonin neurotransmission and progressive white matter pathology. Both heritable genetic factors and environmental factors including dietary fatty-acid composition may act in concert to sustain elevated immune-inflammatory signaling. Collectively, these data suggest that elevated immune-inflammatory signaling is a mechanism that is relevant to the pathoetiology of mood disorders, and may therefore represent a new therapeutic target for the development of more effective treatments.

Compelling evidence suggests that inflammation contributes to the development of depression. Many depressed individuals have higher levels of proinflammatory mediators, which appear to interact with many of the pathophysiological domains of depression, including neuroendocrine function, neurotransmitter metabolism, and synaptic plasticity. This is further supported by observation that therapeutic administration of interferon-α (IFN-α) leads to depression in a significant proportion of patients. These findings suggest that targeting proinflammatory cytokines and their signaling pathways may represent a unique therapeutic opportunity to treat depression and related conditions, such as labile anger, irritability, and fatigue.

In older adults, several environmental challenges can potentially trigger the onset of an episode of major depression. Vulnerability to these challenges can be influenced by genetics. There is accumulating evidence for an interaction between stress and a serotonin transporter polymorphism, though there is also heterogeneity among studies. Other relevant genes include those encoding for the neuroendocrine stress axis, growth factors, and other monoaminergic systems. Each of these may interact with either predisposing traumas in early childhood or precipitating events later in life., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Unipolar major depression is among the leading contributors to the global burden of illness-related disability, and is predicted to be the greatest contributor to illness burden by 2030. It is a matter of public health significance to identify people at high risk for depression and/or already mildly symptomatic, and to discover ways of implementing timely and rational risk reduction strategies to preempt major depression. In this article, the published literature is reviewed to summarize what is known about depression prevention in older adults, and, ultimately, to inform future research., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Interferon-α (IFN-α) treatment for hepatitis C virus (HCV) is complicated by depression and related neurovegetative side effects. Recent genome-wide scans identified IL28B gene polymorphisms that associated with HCV clearance. Whether the IL28B polymorphism is also associated with these adverse effects of IFN-α would affect its clinical usefulness. One hundred thirty-three patients were prospectively examined using the Beck Depression Inventory-II and a Structured Clinical Interview for Diagnostic and Statistical Manual-IV (DSM-IV) during IFN-α treatment. The candidate C/T single-nucleotide polymorphism upstream from IL28B (rs1297860) was genotyped and assessed for association with individual items from the Beck Depression Inventory-II. We confirmed that the IL28B polymorphism was associated with differences in sustained viral response (F = 3.38; P < 0.05), with the T/T genotype faring worst. However, the T/T genotype was associated with less appetite (P < 0.05), energy (P < 0.05), and sleep complaints (P < 0.05) during treatment. Only 3.1% of patients with T/T developed major appetite complaints, whereas 10.1% and 8.9% of those with the C/T and C/C genotype did, respectively. Only 10.8% of patients with T/T developed major sleep complaints, whereas 16.1% and 20.7% of those with the C/T and C/C genotype did. However, IL28B genotype did not predict development of major depressive disorder (χ(2) = 0.12; P = 0.94). The allele (C) was associated with both better viral clearance and more subjective appetite, energy, and sleep complaints. This has implications for the management of patients with HCV. If genotyping is used to better target therapy, this may co-enrich the population for likelihood of also suffering from these side effects.

Objective: Inflammatory cytokines may influence both labile anger and depression. Both psychiatric conditions can occur during interferon alfa-based treatments. Evidence also indicates a central nervous system role for tumor necrosis factor alpha (TNF-alpha), whose expression may be increased by interferon alfa. A polymorphism in the promoter region of TNF-alpha has been associated with various inflammatory illnesses. We therefore hypothesized that this TNF-alpha polymorphism would influence susceptibility to psychiatric symptoms during interferon alfa therapy., Methods: One hundred five patients with hepatitis C, initially without active major depression (major depressive disorder), were treated with interferon alfa and then prospectively monitored using the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, the Beck Depression Inventory II, the Anger Irritability and Assault Questionnaire, and circulating TNF-alpha levels. The A-308G polymorphism (rs1800629) was determined using the 5'-nuclease assay. Repeated-measure mixed-effect analyses compared changes in symptoms over time., Result: Beck Depression Inventory II score increased during interferon alfa therapy (F = 6.2; P < 0.001), with 27% developing MDD. The TNF-alpha A allele was associated with worsened labile anger (F = 2.5; P < 0.05) and fatigue (F = 2.9; P < 0.05) during treatment but not with major depression incidence (chi = 0.0; P = 0.99) or increased Beck Depression Inventory II (F = 1.2; P = 0.31). Labile anger was not predicted by the serotonin transporter polymorphism (F = 0.8; P = 0.59)., Discussion: During treatment with an exogenous cytokine, vulnerability to worsening labile anger-distinct from major depression-is associated with genetic variability in TNF-alpha. This has implications both for patients being treated with interferon alfa and our understanding of genetic vulnerability for different subtypes of dysphoric and mood disorders.

Major depressive disorder (MDD) often occurs during pegylated IFN-alpha2 (IFN-alpha) treatment. Identifying who is at risk for MDD in this population is essential, and epidemiological studies suggest that sleep may be related to depression risk. Controlling for pre-existing depression symptoms, we therefore examined whether sleep quality prior to IFN-alpha treatment would predict subsequent MDD incidence during IFN-alpha treatment. Adults with hepatitis C but without current clinical MDD (n=86) were evaluated prior to IFN-alpha treatment and then prospectively monitored during treatment using self-report measures of sleep quality (PSQI), depression (BDI), and anger and irritability (AIAQ), as well as with Structured Clinical Interviews for DSM-IV Axis I Disorders (SCID-I). During IFN-alpha treatment, 19% developed MDD, 19% developed subsyndromal depression with irritability, and one developed mania. Controlling for baseline depression symptoms and past history of depression, patients with worse sleep quality (PSQI > or = 10) prior to treatment had a significantly shorter time until they developed MDD or any severe psychiatric problem. These findings may have important implications for understanding, predicting, and possibly preventing depression, particularly in individuals treated with IFN-alpha., (Copyright 2009 Elsevier Ireland Ltd. All rights reserved.)

The risk/benefit ratio of pharmacotherapy for behavioral symptoms of dementia is questionable: second-generation antipsychotics are poorly tolerated, and the efficacy of alternative treatments, for example, selective serotonin-reuptake inhibitors (SSRIs), is uncertain. Biomarkers of treatment response may improve this risk/benefit ratio. The length polymorphism of the serotonin transporter promoter gene (5-HTTLPR/SLC6A4) may moderate tolerability of SSRIs and expression of behavioral symptoms in dementia. We assessed the effect of 5-HTTLPR on tolerability and efficacy of citalopram and risperidone in a 12-week randomized controlled trial, which included nondepressed patients with dementia hospitalized for behavioral or psychotic symptoms. Genotypes including the A/G polymorphism of the L allele (rs25531) were determined in 92 of 103 participants. We used pattern-mixture models to account for dropout. Low-expression alleles (S and Lg) predicted greater early and overall side effects of citalopram and early treatment discontinuation. These results remained unchanged after excluding African-American participants and in covariate analyses. Unexpectedly, low-expression alleles seemed to predict greater early side effects of risperidone (but not early discontinuation) and poorer early response of psychosis symptoms to risperidone. In conclusion, 5-HTTLPR may be a useful biomarker of SSRI intolerance in dementia. Our findings of intolerance of a second-generation antipsychotics and persistence of psychosis in patients with low-expression alleles needs to be replicated.

Depressive symptoms, poor sleep quality, and systemic markers of inflammation (e.g., interleukin (IL)-6) are frequently associated. Interferon-alpha (IFN-alpha) therapy results in Major Depressive Disorder (MDD) in some people, offering the possibility to elucidate the relationship of MDD to sleep and inflammation during treatment. In particular, delineating the temporal relations among these factors could help inform their causal relationships. To this end, a cohort of 95 non-depressed hepatitis C patients was followed prospectively for four consecutive months during IFN-alpha therapy. We found that higher pre-treatment levels of circulating IL-6 predicted incidence of MDD (X(2)(1)=7.7; p<0.05). Time-lagged mixed-effect analyses supported uni-directional associations in which IL-6 predicted next month's PSQI scores (F(47,11.6)=78.4; p<0.0005), and PSQI scores predicted next month's depressive Beck Depression Inventory-II (BDI) scores (F(16,22.6)=3.4; p<0.005). In addition, on any given month of treatment, IL-6 levels predicted BDI symptoms the following month (F(16,97.5)=7.3; p<0.0005), and conversely BDI predicted next month's IL-6 (F(14,7.4)=5.2; p<0.05) - providing evidence for a positive feedback relationship between depressive symptoms and systemic inflammation. These data provide further evidence that high levels of inflammation and poor sleep quality may be risk factors for IFN-alpha induced depression. Furthermore, these findings highlight the complex temporal relationships that exist among sleep, depression, and inflammation, and support the need for further prospective investigations to elucidate the dynamics that underlie depression during IFN-alpha treatment.

Background: Major depressive disorder (MDD) occurs in a subset of patients receiving interferon-alpha treatment, although many are resilient to this side effect. Genetic differences in the serotonin reuptake transporter promoter (5-HTTLPR) may interact with the inflammatory system and influence depression risk., Methods: A cohort of 71 nondepressed hepatitis C patients about to receive interferon-alpha was prospectively followed, employing a diagnostic structured clinical interview (Structured Clinical Interview for DSM-IV Axis I Disorders [SCID-I]) and self-report questionnaires. Patients were genotyped for the 5-HTTLPR (L(G), L(A), and S) and the variable number of tandem repeats (VNTR) polymorphism in the second intron. Kaplan-Meier analyses were used to compare major depression incidence. Genotype effects on sleep quality (Pittsburgh Sleep Quality Index) and Beck Depression Inventory (BDI) were assessed using mixed-effect repeated-measure analyses., Results: The L(A) allele was associated with a decreased rate of developing MDD (Mantel-Cox log rank test p < .05) with the L(A)/L(A) genotype being the most resilient. This genotype was also associated with better sleep quality [F(61.2,2) = 3.3, p < .05]. The ability of baseline sleep quality to predict depression incidence disappeared when also including genotype in the model. Conversely, the relationship of neuroticism with depression incidence (B = .07, SE = .02, p < .005) was not mitigated when including genotype., Conclusions: Using a prospective design, 5-HTTLPR is associated with MDD incidence during interferon-alpha treatment. Preliminary evidence that this effect could be mediated by effects on sleep quality was observed. These findings provide support for a possible interaction between inflammatory cytokine (interferon-alpha) exposure and 5-HTTLPR variability in MDD.

Major Depressive Disorder (MDD) during interferon-alpha (IFN-alpha) treatment can occur within a few months of therapy, and shares many homologies with other forms of MDD. Most patients are resilient to the side effect of interferon-induced depression (IFN-MDD), but 15% to 40% are vulnerable. Several studies have employed antidepressants to prevent the incidence of an IFN-MDD episode, and the results suggest that prophylactic antidepressants may be specifically useful in those with pre-existing subthreshold depressive symptoms and/or a history of prior MDD episodes. Several other potential markers of vulnerability for IFN-MDD have been implicated in assessments of nondepressed patients before they start IFN-alpha. These include poor sleep quality, premorbid elevations in inflammatory cytokines, genetic polymorphisms in the serotonin system, personality, and social support. The interplay of these factors strongly predicts who is at risk for IFN-MDD, and indicates several potentially modifiable targets for the personalized prevention of IFN-MDD.

Calcineurin-inhibiting immunosuppressive medications are the mainstay of posttransplant immunosuppression. Although these highly beneficial drugs are critical for posttransplant survival, significant numbers of transplant recipients experience side effects, some requiring a switch to a different immunosuppressive regimen. Neurotoxicity is one of the most debilitating side effects because of its impact on mental status and cognition. As our center uses tacrolimus as the initial immunosuppressant for all liver transplant (LTX) recipients, we were interested in those patients who required a switch because of neurotoxic side effects. Over a 5-year period, 827 adult LTX recipients received their first graft at our center. Ninety-four patients were no longer on tacrolimus by 2 months post-LTX (86 switched because of concerns over neurotoxicity, and 8 switched because of renal function concerns). Of those experiencing neurotoxic side effects, the majority (64%) had altered mental status, and 26% had seizures (first onset post-LTX). On the basis of our prior work, we hypothesized that patients with a pre-LTX history of excessive alcohol use would be at higher risk for neurotoxic effects. We also hypothesized that the elderly and those who had more advanced illness (that is, higher Model for End-Stage Liver Disease scores) at LTX would be at risk as well. We found that patients with a pre-LTX diagnosis of alcoholic liver disease were not more likely to be switched from tacrolimus. Furthermore, we found that in addition to older age and higher Model for End-Stage Liver Disease scores, poorer hepatic functioning was significantly associated with a switch from tacrolimus. We discuss the implications of these findings and the relevance for future clinical care in these high-risk patients.

Late-life depression (LLD) is a common and typically recurrent illness that is often unrecognized and under-treated. It is associated with significant co-morbidities and poor health outcomes. Antidepressants are typically used as a first-line treatment for LLD. We performed a systematic review of the English literature (1996 to August 2007) and present results relevant to the efficacy of antidepressants in acute and maintenance pharmacotherapy of LLD, the predictors of LLD treatment outcomes and pharmacological strategies for non-remission. There is a consensus in the literature that the goal of treatment should be remission. Although antidepressants can be categorized into several classes based on their putative mechanisms of action, there is no consistent evidence that antidepressants from different classes are associated with different rates of remission of LLD. After achieving remission, the evidence supports a beneficial role of maintenance pharmacotherapy in reducing the rate of recurrence of LLD for at least 2 years. There are reports of a number of possible augmentation and switching strategies that can be used when LLD remission is not attained. However, none of these various strategies has been studied rigorously in patients with LLD as yet. Overall, the current literature is adequate for guiding acute and maintenance pharmacotherapy of LLD but further research is urgently needed to guide clinical strategies in non-remission.

Clinical and epidemiological studies have consistently observed the heterogeneous symptomatology and course of geriatric depression. Given the importance of genetic and environmental risk factors, aging processes, neurodegenerative and cerebrovascular disease processes, and medical comorbidity, the integration of basic and clinical neuroscience research approaches is critical for the understanding of the variability in illness course, as well as the development of prevention and intervention strategies that are more effective. These considerations were the impetus for a workshop, sponsored by the Geriatrics Research Branch in the Division of Adult Translational Research and Treatment Development of the National Institute of Mental Health that was held on September 7-8, 2005. The primary goal of the workshop was to bring together investigators in geriatric psychiatry research with researchers in specific topic areas outside of geriatric mental health to identify priority areas to advance translational research in geriatric depression. As described in this report, the workshop focused on a discussion of the development and application of integrative approaches combining genetics and neuroimaging methods to understand such complex issues as treatment response variability, the role of medical comorbidity in depression, and the potential overlap between depression and dementia. Future directions for integrative research were identified. Understanding the nature of geriatric depression requires the application of translational research and interdisciplinary research approaches. Geriatric depression could serve as a model for translational research integrating basic and clinical neuroscience approaches that would have implications for the study of other neuropsychiatric disorders.

Objective: Interferon-alpha2 (IFN-alpha) injections may be capable of triggering depression in some individuals. The first objective was to further characterize this depression and, secondly, to examine whether pre-treatment temperament was correlated with subsequent vulnerability to IFN-alpha., Methods: Twenty-three initially euthymic adults undergoing year-long PEG-IFN-alpha treatment for hepatitis C were evaluated at baseline and then prospectively monitored using both the Structured Clinical Interview for DSM-IV (SCID) and self-report questionnaires., Results: A major depressive episode developed within 3 months in 39%. Principal component analysis of the change in self-report scores after 1 month of treatment demonstrated three orthogonal factors: (i) a specific increase in depression as manifested in the Beck Depression Inventory (BDI) and Hospital Anxiety and Depression Scale (HADS), (ii) an increase in hostility and anxiety, (iii) and a generalized combination of worse symptoms including somatic symptoms on the Symptom Check List (SCL-90). BDI at 1 month was predicted by baseline BDI (r=0.76, P=.004). Hostility at 1 month was predicted by low baseline agreeableness (r=0.75, P=.01). Controlling for baseline BDI scores, categorical major depression was predicted by combined high baseline neuroticism and low agreeableness (combined r=0.66, P=.03)., Conclusion: These initial results (i) support the depressogenic nature of IFN-alpha treatment in a subset of vulnerable individuals, (ii) indicate that some individuals are also independently vulnerable to worsened hostility, and (iii) suggest that it may be possible to clinically predict these vulnerabilities in initially euthymic subjects.

Single nucleotide polymorphism (SNP) genotype frequencies were examined to determine whether variation in 6 estrogen-related genes was associated with differences in self-reported depressive symptoms in women. In this substudy of the Study of Women's Health Across the Nation (SWAN), DNA from a multiracial/multiethnic sample of 1,538 African American, Caucasian, Chinese, and Japanese women aged 42 to 52 years participating in SWAN was genotyped. Depressive symptoms were measured with the Center for Epidemiologic Studies-Depression (CES-D) scale. After excluding data from women taking antidepressants (n=103), statistical models were fit using multivariate logistic regression to predict the association of estrogen-related polymorphisms with the dichotomized CES-D score. Among Caucasian women, those with the CYP1A1 rs2606345 CC and AC genotypes had approximately 2-fold greater odds of having depressive symptoms than did those with the AA genotype (95% confidence intervals [CIs], 1.33 to 4.66 and 1.25 to 3.14, respectively). African American women with the CC genotype of the same SNP had 10-fold greater odds of having more depressive symptoms than did women with the AA genotype (95% CI, 1.20 to 86.20). In Japanese women, the odds of depressive symptoms were nearly 5-fold higher among those with CYP 19 rs936306 TT genotype (95% CI, 1.10 to 22.17) than in women with the CC genotype and 9.6-fold higher (95% CI, 2.01 to 45.81) than in women with the CT genotype. The odds of depressive symptoms among Chinese women with the 17HSD rs615942 TT genotype were nearly 11-fold higher than in those with the GT genotype (95% CI, 1.94 to 60.84) and >7-fold higher than in those with the GG genotype (95% CI, 1.13 to 51.82). These data provide evidence that selected genes involved in estrogen synthesis and metabolism increase the odds of more depressive symptoms in women who are premenopausal or perimenopausal.

Pharmacodynamic differences are difficult to interpret without drug concentration data. In particular, variability in drug exposure may confound the interpretation of pharmacogenetic, therapeutic outcome, and neuroimaging studies. Inter-individual variability in concentrations can be quite high due to variable adherence and pharmacokinetics. For example, clearance may be influenced by genetics, drug interactions, age and illness. We review findings that acute responses to selective serotonin reuptake inhibitors can have a concentration-response relationship using positron emission tomography and neuroendocrine measures. We also present preliminary evidence that the concentration-response relationship for paroxetine is influenced by genotypic differences at the serotonin transporter promoter. In large clinical studies, the accurate assessment of drug exposure can be challenging, with several techniques used to assess exposure. Population pharmacokinetics (Pop PK) is a method that is ideally suited for analysing concentration data from large trials because both patient-specific and population parameters can be determined with only a small number of plasma samples per patient. As opposed to relying on prescribed doses or a single trough level, the ability to determine more accurately exposure with Pop PK reduces the heterogeneity introduced by exposure variability. Pop PK hierarchic Bayesian approaches have been effective for characterizing anticonvulsants, antibiotics, antineoplastics and antiarrhythmics. We have recently successfully incorporated these pop PK analyses into routine assessments of elderly patients in clinical trials of selective serotonin reuptake inhibitors (SSRIs) and second generation antipsychotics. For the design and interpretation of neuroimaging, pharmacogenetic, and behavioural studies, the assessment of drug concentration exposure is therefore feasible and has potentially important ramifications.

Introduction: Dextromethorphan is a commonly used antitussive agent that can be purchased over the counter. It is metabolized primarily by the cytochrome P450 (CYP) 2D6 isozyme. Methadone has been found to inhibit CYP2D6, indicating a potential for interaction with dextromethorphan., Case Summary: An 83-year-old woman was evaluated for delirium, hypersomnia, confusion, lethargy, impaired concentration, and poor food intake. Symptoms resolved soon after discontinuing dextromethorphan., Discussion: Vulnerability to delirium was potentially caused by coadministration of methadone, which can inhibit the CYP2D6 isozyme., Conclusion: Evaluation of delirium should include close investigation of the patient's medications for potential interactions with dextromethorphan.

Selective serotonin reuptake inhibitors (SSRIs) can safely and successfully treat major depression, although a substantial number of patients benefit only partially or not at all from treatment. Genetic polymorphisms may play a major role in determining the response to SSRI treatment. Nonetheless, it is likely that efficacy is determined by multiple genes, with individual genetic polymorphisms having a limited effect size. Initial studies have identified the promoter polymorphism in the gene coding for the serotonin reuptake transporter as moderating efficacy for several SSRIs. The goal of this review is to suggest additional plausible polymorphisms that may be involved in antidepressant efficacy. These include genes affecting intracellular transductional cascades; neuronal growth factors; stress-related hormones, such as corticotropin-releasing hormone and glucocorticoid receptors; ion channels and synaptic efficacy; and adaptations of monoaminergic pathways. Association analyses to examine these candidate genes may facilitate identification of patients for targeted alternative therapies. Determining which genes are involved may also assist in identifying future, novel treatments.

Rationale: The neuroendocrine response to intravenous citalopram may provide an acute, functional, in vivo measure of the neural serotonin (5-HT) system., Objective: To refine the quantification of acute neuroendocrine responses following intravenous citalopram in studies of 5-HT function., Methods: In 75 adult healthy subjects taking part in four similar protocols, we measured plasma prolactin and cortisol, as well as serial citalopram concentrations following intravenous citalopram (10 mg, 20 mg, 40 mg, 0.33 mg/kg) and placebo. The relationship between the AUC for intravenous citalopram during the first 150 min (AUC(150)) and the magnitude of the neuroendocrine response was determined. The role of pharmacokinetic (PK) parameters, as well as sensitivity to placebo injections, in influencing the neuroendocrine response to citalopram was then evaluated., Results: Citalopram produced a dose-dependent increase in cortisol and prolactin. The maximal increase from baseline correlated significantly but modestly with citalopram's AUC(150) (prolactin r(2)=0.23, P<0.0001; cortisol r(2)=0.3, P<0.0001). Additionally, citalopram's AUC(150) was affected by between-subject differences in both the peripheral and central volume of distribution. However, the neuroendocrine responses to citalopram did not correlate with the responses to placebo., Conclusions: The parenteral citalopram challenge test is characterized by a modest concentration-response relationship, with concentration influenced by variable PK factors. Accounting for individual differences in drug distribution may improve the power of the citalopram challenge test, when used as an in vivo measure of central 5-HT function.

The serotonin transporter promoter polymorphism (5-HTTLPR) has been associated with vulnerability to stress-induced depressive symptoms and with the speed and rate of response to antidepressant treatment. The goal of the present study was to evaluate the association between the 5-HTTLPR and the functional response of the serotonin system as measured by the neuroendocrine and cerebral metabolic response to intravenous administration of the selective serotonin reuptake inhibitor citalopram in normal control subjects. Genotyping was performed for 5-HTTLPR insertion/deletion polymorphism long (l) and short (s) variant alleles. The ll genotype was compared with the combined sl+ss and with the ss genotype alone. Citalopram plasma concentrations did not differ significantly between groups. The s allele was associated with a less of an increase in prolactin and cortisol than the ll genotype. The s allele was associated with greater decreases in left frontal, precentral and middle temporal gyri compared to the ll genotype. The ll genotype was associated with greater decreases in right frontal, insula and superior temporal gyrus compared to the ss genotype. These findings suggest that 5-HTTLPR is associated with an altered functional response of the serotonin system, which may represent a neurobiologic substrate for the differential response to antidepressant treatment in late life and the emergence of neuropsychiatric symptoms in neurodegenerative disorders.

Polymorphisms in the promoter region (5-HTTLPR) of the serotonin transporter and a variable number of tandem repeats polymorphism in the second intron have been widely studied. However, the results of association studies examining unipolar depression (MDD) or bipolar disorder depression (BPD) have been mixed. To precisely ascertain small associations with both polymorphisms, a meta-analysis was performed involving several thousand subjects, using random-effects modeling. For MDD, the effect of the 5-HTTLPR genotype was significant (chi2=6.1, P<0.05), with 21% of MDD subjects and 17% of controls homozygous for the short (S) allele (odds ratio, 1.16). Similar findings were noted in BPD, with a higher frequency of S/S genotypes in affected patients, although the results did not reach statistical significance. Results of transmission disequilibrium tests trended in a similar direction but also did not reach statistical significance. No consistent effect of the variable number of tandem repeats polymorphism was revealed for either MDD or BPD. The results suggest that the S allele, or a neighboring allele in linkage disequilibrium, is recessive for MDD and possibly BPD. Notably, the association is very small. With these small associations, confounding issues such as population stratification require addressing. Significant heterogeneity between studies was also evident, possibly reflecting differences in diagnosis, different control populations, and different ethnic populations. These factors should Influence the interpretation of the association found in this analysis.

Background: Americans of African ancestry are less likely to receive a selective serotonin reuptake inhibitor (SSRI) for treatment of major depressive disorder than Americans of European ancestry. A functional insertion/deletion polymorphism in the promoter of the serotonin transporter (5-HTT) gene SLC6A4 has been shown to modulate SLC6A4 transcription, affecting response to SSRIs. Several studies in populations of predominantly European ancestry have consistently found that the SLC6A4 promoter polymorphism (referred to as the 5-HTT-linked polymorphic region; 5-HTTLPR) long (L) allele is associated with better response to SSRI treatment than the short (S) allele., Objective: The frequency of SLC6A4 (5-HTTLPR) alleles in 865 black Americans and Afro-Caribbeans was examined to assess possible implications for treatment., Study Design and Methods: SLC6A4 (5-HTTLPR) genotypes were determined in individuals with self-identified African ancestry from South Carolina (n = 489), western Pennsylvania (n = 207), and Tobago (n = 169). Frequencies were compared using chi-square analyses., Results: It was verified that the L allele is highly prevalent in Americans of African ancestry, ranging from 77% in western Pennsylvania to 87% in South Carolina. The frequency of the SLC6A4-(L) allele is significantly higher in African-Americans than has been reported for European-Americans (typically 56-60%). There are both statistically significant geographic differences and slight deviations from Hardy-Weinberg equilibrium., Conclusions: Given the potential influence on treatment response, these findings have implications for the use of SSRIs in this population. The results suggest that additional studies to examine the impact of these alleles on treatment response in African-Americans are warranted.

Selective serotonin reuptake inhibitors (SSRIs) are used to treat a number of psychiatric disorders related to mood and anxiety, and variations in the serotonin transporter (5-HTT) gene may be involved in a number of these. A polymorphic site in the promoter region is associated with differences in 5-HTT gene expression. Studies suggest that the short allele of the 5-HTT promoter (5-HTTPR) site can adversely influence the antidepressant response to SSRIs, and is associated with anxiety-related traits, depression, and impulsive disorders such as alcohol abuse. Several studies do not replicate these findings; potential confounding factors include age, gender, and population stratification. Other 5-HTT polymorphisms also exist. For example, individuals with the short allele of a variable number of tandem repeats (VNTR) polymorphism, located in the second intron, may have reduced responsiveness to SSRIs, and the STin2.12 allele at this site has been associated with bipolar disorder. Findings both supporting and inconsistent with these conclusions are reviewed. The clinical effects of the polymorphisms may be associated with effects on platelets, neural 5-HTT levels, and indices of serotonergic function.