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For the past 5 years, many investigators have suggested that psychiatrists are on the verge of using genotyping to guide clinical psycho-pharmacological practice. After much anticipation, the first applications of this new technology are being used to select psychotropic medication and inform individual variation in the appropriate dose of medication. Not surprisingly, the drug-metabolizing enzyme genes have been the first genes to be clinically genotyped for psychiatric practice.

Aims Citalopram (CT) and escitalopram (S-CT) are among the most widely prescribed selective serotonin reuptake inhibitors used to treat major depressive disorder (MDD). We applied a genome-wide association study to identify genetic factors that contribute to variation in plasma concentrations of CT or S-CT and their metabolites in MDD patients treated with CT or S-CT. Methods Our genome-wide association study was performed using samples from 435 MDD patients. Linear mixed models were used to account for within-subject correlations of longitudinal measures of plasma drug/metabolite concentrations (4 and 8 weeks after the initiation of drug therapy), and single-nucleotide polymorphisms (SNPs) were modelled as additive allelic effects. Results Genome-wide significant associations were observed for S-CT concentration with SNPs in or near the CYP2C19 gene on chromosome 10 (rs1074145, P = 4.1 × 10−9) and with S-didesmethylcitalopram concentration for SNPs near the CYP2D6 locus on chromosome 22 (rs1065852, P = 2.0 × 10−16), supporting the important role of these cytochrome P450 (CYP) enzymes in biotransformation of citalopram. After adjustment for the effect of CYP2C19 functional alleles, the analyses also identified novel loci that will require future replication and functional validation. Conclusions In vitro and in vivo studies have suggested that the biotransformation of CT to monodesmethylcitalopram and didesmethylcitalopram is mediated by CYP isozymes. The results of our genome-wide association study performed in MDD patients treated with CT or S-CT have confirmed those observations but also identified novel genomic loci that might play a role in variation in plasma levels of CT or its metabolites during the treatment of MDD patients with these selective serotonin reuptake inhibitors.

Adverse events, response failures and medication non-compliance are common in patients receiving medications for the treatment of mental illnesses. A systematic literature review assessed whether pharmacokinetic (PK) or pharmacodynamic (PD) responses to 26 commonly prescribed antipsychotic and antidepressant medications, including efficacy or side effects, are associated with nucleotide polymorphisms in eight commonly studied genes in psychiatric pharmacotherapy: CYP2D6, CYP2C19, CYP2C9, CYP1A2, CYP3A4, HTR2C, HTR2A, and SLC6A4. Of the 294 publications included in this review, 168 (57%) showed significant associations between gene variants and PK or PD outcomes. Other studies that showed no association often had insufficient control for confounding variables, such as co-medication use, or analysis of medications not substrates of the target gene. The strongest gene-outcome associations were for the PK profiles of CYP2C19 and CYP2D6 (93% and 90%, respectively), for the PD associations between HTR2C and weight gain (57%), and for SLC6A4 and clinical response (54%), with stronger SLC6A4 response associations for specific drug classes (60-83%). The preponderance of evidence supports the validity of analyzing nucleotide polymorphisms in CYP and pharmacodynamic genes to predict the metabolism, safety, or therapeutic efficacy of psychotropic medications commonly used for the treatment of depression, schizophrenia, and bipolar illness.

Background The role of the promoter polymorphism (5HTTLPR) of the serotonin transporter gene (SLC6A4) in psychiatric illnesses has been studied extensively. Serotonergic function also regulates many central nervous system, including appetite and feeding behaviors. The 5HTTLPR short allele was found to be associated with increased body mass index and obesity risk among the general population. No data is available to support generalizability of such association among psychiatric population. Methods We examined the relationship between BMI and the 5HTTLPR genotype in a large sample of 1831 psychiatric patients at Mayo Clinic, Rochester, Minnesota, using a retrospective chart review. Results Average BMI among groups with the short/short (28.29±7.27 kg/m 2 ), the short/long (28.07±6.45 kg/m 2 ) and the long/long (28.15±7.51 kg/m 2 ) genotypes of 5HTTLPR were not statistically different. This negative association persisted even with the sub-analysis of the Caucasians. However, we observed an increased rate of obesity among our psychiatric patient sample compared to the general population of Minnesota (36.6% versus 27.6%, p =0.0001 for males, 30.3% versus 24.4%, p =0.0001 for females). Also, sub-analysis showed female inpatients to have a significantly higher average BMI than outpatients (28.64±8.08 kg/m 2 versus 27.13±6.92 kg/m 2 , p =0.026). This confirmed a significant association between mental health disorder and BMI. Limitations Retrospective study design with limited control for potential confounders. Conclusions In this large sample of psychiatric patients we found no significant association between 5HTTLPR genotype and BMI, which is different from the case with general population reported in the literature.

Synthetic κ-opioid receptor (KOR) agonists induce dysphoric and pro-depressive effects and variations in the KOR (OPRK1) and prodynorphin (PDYN) genes have been shown to be associated with alcohol dependence. We genotyped 23 single nucleotide polymorphisms (SNPs) in the PDYN and OPRK1 genes in 816 alcohol-dependent subjects and investigated their association with: (1) negative craving measured by a subscale of the Inventory of Drug Taking Situations; (2) a self-reported history of depression; (3) the intensity of depressive symptoms measured by the Beck Depression Inventory-II. In addition, 13 of the 23 PDYN and OPRK1 SNPs, which were previously genotyped in a set of 1248 controls, were used to evaluate association with alcohol dependence. SNP and haplotype tests of association were performed. Analysis of a haplotype spanning the PDYN gene (rs6045784, rs910080, rs2235751, rs2281285) revealed significant association with alcohol dependence (p = 0.00079) and with negative craving (p = 0.0499). A candidate haplotype containing the PDYN rs2281285-rs1997794 SNPs that was previously associated with alcohol dependence was also associated with negative craving (p = 0.024) and alcohol dependence (p = 0.0008) in this study. A trend for association between depression severity and PDYN variation was detected. No associations of OPRK1 gene variation with alcohol dependence or other studied phenotypes were found. These findings support the hypothesis that sequence variation in the PDYN gene contributes to both alcohol dependence and the induction of negative craving in alcohol-dependent subjects.

Background and Objectives The aim of this study was to investigate potential gender differences in situations associated with heavy alcohol drinking. Methods Data from 395 alcohol dependent patients participating in the Mayo Clinic Intensive Addiction Program were evaluated. Each participant completed the inventory of drug taking situations (IDTS), Penn alcohol craving scale (PACS), patient health questionnaire (PHQ-9), and/or Beck depression inventory (BDI). Gender differences in IDTS scores representing three domains (negative, positive, and temptation) of situations associated with heavy alcohol use were examined. Results Women with alcohol dependence report a higher frequency of heavy drinking in unpleasant emotional (IDTS negative scores mean ± SD women vs. men: 52.3 ± 22.1 vs. 43.8 ± 21.8; p = .0006), and as a result of temptation (IDTS temptation scores mean ± SD women vs. men: 40.4 ± 23.0 vs. 35.3 ± 20.8; p = .035). Upon admission, women also scored significantly higher on depressive symptoms as measured by the BDI (23.4 ± 11.4 vs. 18.2 ± 9.8, p

FKBP51 (51 kDa immunophilin) acts as a modulator of the glucocorticoid receptor and a negative regulator of the Akt pathway. Genetic variation in FKBP5 plays a role in antidepressant response. The aim of this study was to comprehensively assess the role of genetic variation in FKBP5, identified by both Sanger and Next Generation DNA resequencing, as well as genome-wide single nucleotide polymorphisms (SNPs) associated with FKBP5 expression in the response to the selective serotonin reuptake inhibitor (SSRI) treatment of major depressive disorder.We identified 657 SNPs in FKBP5 by Next Generation sequencing of 96 DNA samples from white patients, and 149 SNPs were selected for the genotyping together with 235 SNPs that were trans-associated with variation in FKBP5 expression in lymphoblastoid cells. A total of 529 DNA samples from the Mayo Clinic PGRN-SSRI Pharmacogenomic trial for which genome-wide SNPs had already been obtained were genotyped for these 384 SNPs, and associations with treatment outcomes were determined. The most significant SNPs were genotyped using 96 DNA samples from white non-Hispanic patients of the NIMH-supported Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study to attempt replication, followed by functional genomic studies.Genotype-phenotype association analysis indicated that rs352428 was associated with both 8-week treatment response in the Mayo study (odds ratio=0.49; P=0.003) and 6-week response in the STAR*D replication study (odds ratio=0.74; P=0.05). The electrophoresis mobility shift assay and the reporter gene assay confirmed the possible role of this SNP in transcription regulation.This comprehensive FKBP5 sequence study provides insight into the role of common genetic polymorphisms that might influence SSRI treatment outcomes in major depressive disorder patients.

Background and Objectives: Alcoholism treatment interventions, both psychosocial and pharmacologic, aim to reduce cravings to drink. Yet, the role of craving in treatment outcomes remains unclear. This study evaluated craving intensity measured with the Penn Alcohol Craving Scale (PACS) at admission and discharge from residential treatment as a predictive factor of relapse after treatment. Methods: The study cohort included 314 alcohol-dependent subjects. Associations between relapse after discharge, PACS score, and clinical variables were investigated using time-to-event analyses. The primary analysis, based on the intent-to-treat principle, presumed relapse in those declining follow-up or not responding to contact attempts. Secondary analysis utilized data from 226 subjects successfully contacted after discharge with a median follow-up time of 365 days. Results: The intent-to-treat analysis demonstrated that relapse was associated with higher level of craving at admission (p= .002) and discharge (p < .001). The analysis of data from patients successfully contacted after discharge led to similar results. A multivariable analysis indicated that relapse rates increased as PACS scores increased, and a higher discharge PACS score was significantly associated with relapse (p= .006) even after adjusting for covariates. Conclusions and Scientific Significance: This study demonstrates that higher PACS scores at the time of admission and discharge are associated with relapse following residential addiction treatment. These data support the role of craving in relapse and the utility of craving measurement as a clinical guide in assessing relapse risk. (Am J Addict 2012;21:S20–S26)

A genome-wide association (GWA) study of treatment outcomes (response and remission) of selective serotonin reuptake inhibitors (SSRIs) was conducted using 529 subjects with major depressive disorder. While no SNP associations reached the genome-wide level of significance, 14 SNPs of interest were identified for functional analysis. The rs11144870 SNP in the riboflavin kinase (RFK) gene on chromosome 9 was associated with 8-week treatment response (odds ratio (OR)=0.42, P=1.04 × 10⁻⁶). The rs915120 SNP in the G protein-coupled receptor kinase 5 (GRK5) gene on chromosome 10 was associated with 8-week remission (OR=0.50, P=1.15 × 10⁻⁵). Both SNPs were shown to influence transcription by a reporter gene assay and to alter nuclear protein binding using an electrophoretic mobility shift assay. This report represents an example of joining functional genomics with traditional GWA study results derived from a GWA analysis of SSRI treatment outcomes. The goal of this analytical strategy is to provide insights into the potential relevance of biologically plausible observed associations.

To further explore reports of association of alcohol dependence and response to acamprosate treatment with the GATA4 rs13273672 single nucleotide polymorphism (SNP), we genotyped this and 10 other GATA4 SNPs in 816 alcohol-dependent cases and 1248 controls. We tested for association of alcohol dependence with the 11 SNPs individually and performed a global test for association using a principle components analysis. Our analyses demonstrate significant association between GATA4 and alcohol dependence at the gene level (P = 0.009) but no association with rs13273672. Further studies are needed to identify potential causal GATA4 variation(s) and the functional mechanism(s) contributing to this association.

Acamprosate is clinically used to treat alcohol-dependent patients. While the molecular and pharmacological mechanisms of acamprosate remain unclear, it has been shown to regulate γ-aminobutyric acid (GABA) or glutamate levels in the cortex and striatum. To investigate the effect of acamprosate on brain metabolites in the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc), we employed in vivo 16.4 T proton magnetic resonance spectroscopy. We utilized type 1 equilibrative nucleoside transporter (ENT1) null mice since acamprosate attenuates ethanol drinking in these mice. Our findings demonstrated that ethanol withdrawal reduced GABA levels and increased phosphorylated choline compounds in the mPFC of both wild-type and ENT1 null mice. Notably, acamprosate normalized these withdrawal-induced changes only in ENT1 null mice. In the NAc, ethanol withdrawal increased glutamate and glutamine (Glx) levels only in wild-type mice. Interestingly, acamprosate reduced Glx levels in the NAc compared to the withdrawal state in both genotypes. These results provide a molecular basis for the pharmacological effect of acamprosate in the cortical-striatal circuit.

This review evaluates the utilization of pharmacogenomic testing to guide treatment with antipsychotic medications as well as the evidence supporting the use of pharmacogenomic testing. There are two basic objectives for using pharmacogenomic testing. The first pharmacogenomic objective is to minimize adverse effects. The second pharmacogenomic objective is to improve clinical outcomes. While available pharmacogenomic testing has been demonstrated to increase the likelihood of achieving a good response, the primary current indication is to improve patient safety.

Trazodone is one of the most commonly prescribed hypnotic medications in patients with sleep disturbances in alcohol recovery. A recent study concluded that treating insomnia with trazodone in patients with alcohol dependence might impede improvements in alcohol consumption and lead to increased drinking when trazodone is stopped. We set out to investigate the relationship between trazodone use during alcoholism treatment and relapse rates in patients who were discharged from a residential alcohol treatment program. We retrospectively reviewed records of patients with a diagnosis of alcohol dependence in a residential addiction treatment center from 2005 to 2008 and analyzed the association of trazodone use at discharge and alcohol relapse at 6 months. We also assessed the association between trazodone use and relapse at 6 months adjusting for sex, drug dependence, nonsubstance use Axis I psychiatric diagnoses, patient self-report of difficulties with sleep, and anti-dipsotropic medication use at discharge and evaluated pair-wise interactions of trazodone use with the adjustment variables. Of 283 patients eligible for inclusion, 85 (30%) were taking trazodone at discharge. Older age, self-reported sleep problems, and having a nonsubstance use Axis I psychiatric diagnosis were associated with trazodone use. After discharge, 170 (60%) subjects responded to follow-up efforts. Neither intent to treat nor responder only analysis revealed any association between trazodone use and relapse. Our retrospective study of a complex patient population discharged from a residential treatment setting did not find an association between trazodone use at discharge and relapse rates at 6 months.

Background: Several polymorphisms in FK506 Binding Protein gene (FKBP5) and a history of child abuse have been shown to be associated with an increased risk for posttraumatic stress disorder (PTSD). It has also been demonstrated that the same polymorphisms of FKBP5 are associated with increased recurrence of depressive episodes and rapid response to antidepressant treatment. However, there are only limited numbers of studies replicating the polymorphisms as vulnerability factors for the development of mental illnesses, such as PTSD and depression after stressful life event, especially with a specific incidence, such as kidney transplant surgery. Methods: A retrospective analysis was conducted using the electronic medical records of 131 adult kidney transplant recipients. Depression severity after kidney transplantation was measured by PHQ-9, and stored blood was genotyped for variants in the Serotonin Transporter (SLC6A4), Brain-Derived Neurotrophic Factor, Catecholamine-O-Methyltransferase, Corticotropin-Releasing Hormone Receptor, and FKBP5 genes. Spearman correlations were used to test for association between genetic variants and depression severity. Results: The rare alleles at three out of four SNPs in FKBP5 (rs1360780, rs9296158, and rs9470080) were associated with increased PHQ-9 scores (Po.05), whereas the last FKBP5 SNP (rs3800373) showed a trend of association (Po.10). All four FKBP5 SNPs are in strong linkage disequilibrium. Although in a subgroup of Caucasian non-Hispanic subjects the association was not statistically significant, the direction of association was consistent with that observed in the entire sample as well as in previous studies. Polymorphisms in genes other than FKBP5 were not associated with PHQ-9 scores. Conclusions: Polymorphisms in FKBP5 may be associated with higher depression scores in kidney transplant recipients. Depression and Anxiety 28:1111–1118, 2011. r 2011 Wiley Periodicals, Inc.

Model studies in mice indicate that the severity of alcohol withdrawal is associated with polymorphic variation and expression of the MPDZ gene. Current knowledge about variation in the human MPDZ gene is limited; however, our data indicate its potential association with alcohol dependence. The multi-PDZ protein is an important part of the N-methyl-D-aspartate (NMDA)-dependent α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor trafficking cascade that controls glutamate-related excitatory neurotransmission. To investigate association of variation in the NMDA-dependent AMPA trafficking cascade with alcohol dependence, we performed a gene-set (pathway) analysis using single nucleotide polymorphism (SNP) data from the Study of Addiction: Genetic and Environment. Rather than testing for association with each SNP individually, which typically has low power to detect small effects of multiple SNPs, gene-set analysis applies a single statistical test to evaluate whether variation in a set of genes is associated with the phenotype of interest. Gene-set analysis of 988 SNPs in 13 genes in the pathway demonstrated a significant association with alcohol dependence, with P < 0.01 for the global effect of variation in this pathway. The statistically significant association of alcohol dependence with genetic variation in the NMDA-dependent AMPA receptor trafficking cascade indicates a need for further investigation of the role of this pathway in alcohol dependence.

Alcohol consumption is associated with a broad array of physiologic and behavioral effects including changes in heart rate. However, the physiologic mechanisms of alcohol effects and the reasons for individual differences in the cardiac response remain unknown. Measuring changes in resting heart rate (measured as beats/min) has not been found to be as sensitive to alcohol’s effects as changes in heart rate variability (HRV). HRV is defined as fluctuations in interbeat interval length which reflect the heart’s response to extracardiac factors that affect heart rate. HRV allows simultaneous assessment of both sympathetic and parasympathetic activity and the interplay between them. Increased HRV has been associated with exercise and aerobic fitness, while decreased HRV has been associated with aging, chronic stress, and a wide variety of medical and psychiatric disorders. Decreased HRV has predictive value for mortality in general population samples and patients with myocardial infarction and used as an indicator of altered autonomic function. A significant inverse correlation was found between HRV and both the severity of depression and the duration of the depressive episode. HRV analysis provides insights into mechanisms of autonomic regulation and is extensively used to clarify relationships between depression and cardiovascular disease. This article will review the methodology of HRV measurements and contemporary knowledge about effects of acute alcohol consumption on HRV. Potential implications of this research include HRV response to alcohol that could serve as a marker for susceptibility to alcoholism. At present however there is almost no research data supporting this hypothesis.

Objective Variations in cytochrome P450 (CYP) genes have been shown to be associated with both accelerated and delayed pharmacokinetic clearance of many psychotropic medications. Citalopram is metabolized by three CYP enzymes. CYP2C19 and CYP3A4 play a primary role in citalopram metabolism, whereas CYP2D6 plays a secondary role. Methods The Sequenced Treatment Alternatives to Relieve Depression sample was used to examine the relationship between variations in the CYP2C19 and CYP2D6 genes and remission of depressive symptoms and tolerance to treatment with citalopram. The primary analyses were of the White non-Hispanic patients adherent to the study protocol (n= 1074). Results Generally, patients who had CYP2C19 genotypes associated with decreased metabolism were less likely to tolerate citalopram than those with increased metabolism, although this difference was not statistically significant (P = 0.06). However, patients with the inactive 2C19*2 allele had significantly lower odds of tolerance (P = 0.02). Patients with the poor metabolism CYP2C19 genotype-based category who were classified as citalopram tolerant were more likely to experience remission (P = 0.03). No relationship between CYP2D6 genotype-based categories and either remission or tolerance was identified, although exploratory analyses identified a potential interaction between CYP2C19 and CYP2D6 effects. Conclusion Despite several limitations including the lack of serum drug levels, this study showed that variations in CYP2C19 were associated with tolerance and remission in a large sample of White non-Hispanic patients treated with citalopram.

this article reviews the current status and recent trends in the American Board of Psychiatry and Neurology (ABPN) psychiatric subspecialties and discusses the implications of those trends as well as several key questions whose answers may well determine subspecialty viability.data are presented on specialty and subspecialty programs; graduates; and ABPN certification candidates and diplomates drawn from several sources, including the records of the ABPN, the websites of the Accreditation Council for Graduate Medical Education and the American Medical Association, and the annual medical education issues of JAMA.fewer than half of psychiatry graduates pursue subspecialty training. While most recent specialty graduates attempt to become certified by the ABPN, many subspecialists elect not to do so. There have been recent decreases in the number of fellowship programs and trainees in geriatric psychiatry and addiction psychiatry. The pass rates for fellowship graduates are superior to those for the "grandfathers" in all of the newer psychiatric subspecialties. Lower percentages of subspecialists than specialists participate in maintenance of certification, and maintenance of certification pass rates are high.the initial interest in training and certification in some of the ABPN subspecialties appears to have slowed, and the long-term viability of those subspecialties may well depend on the answers to a number of complicated social, economic, and political questions in the new health care era.

Major depressive disorder (MDD) is a common psychiatric disease. Selective serotonin reuptake inhibitors (SSRIs) are an important class of drugs used in the treatment of MDD. However, many patients do not respond adequately to SSRI therapy. We used a pharmacometabolomics-informed pharmacogenomic research strategy to identify citalopram/escitalopram treatment outcome biomarkers. Metabolomic assay of plasma samples from 20 escitalopram remitters and 20 nonremitters showed that glycine was negatively associated with treatment outcome (P = 0.0054). This observation was pursued by genotyping tag single-nucleotide polymorphisms (SNPs) for genes encoding glycine synthesis and degradation enzymes, using 529 DNA samples from SSRI-treated MDD patients. The rs10975641 SNP in the glycine dehydrogenase (GLDC) gene was associated with treatment outcome phenotypes. Genotyping for rs10975641 was carried out in 1,245 MDD patients in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, and its presence was significant (P = 0.02) in DNA taken from these patients. These results highlight a possible role for glycine in SSRI response and illustrate the use of pharmacometabolomics to "inform" pharmacogenomics.

Despite the high prevalence rate of comorbid alcohol dependence and bipolar disorder, little is known about how many bipolar patients are actively engaged in addiction treatment or the alcohol consumption characteristics of this group. This retrospective study reviewed the medical records from patients with alcohol dependence admitted to residential treatment at our institution (n = 588). The analyses focused on alcoholism severity measures and discharge clinical diagnoses. Patients with alcoholism + bipolar disorder compromised only 5% of the total study group. The number of drinking years was lower for patients with alcoholism + bipolar disorder (23.1 ± 17.7) than for those with alcoholism + depression (26.8 ± 13.9) or alcoholism alone (28.1 ± 13.2). A trend of higher mean lifetime maximum daily drinks was observed for patients with alcoholism + bipolar disorder; this was because of the significantly higher maximum drinks for women with bipolar disorder (21.0 ± 11.5) than for women in other diagnostic groups. Despite high rates of comorbidity in community-based studies, this retrospective study suggests that patients with bipolar disorder are not highly represented in residential alcoholism addiction treatment. Future studies are encouraged to better understand utilization rates of addiction treatment among patients with bipolar disorder and to identify clinical correlates that predispose bipolar women to high-dose drinking.

Response to psychiatric medications in later life is highly heterogeneous and complex. Monoaminergic-related polymorphisms may influence medication response and susceptibility to side effects in elderly individuals. Individuals with the lower function short (S) allele of the serotonin transporter gene (SLC6A4) insertion/deletion (indel) promoter polymorphism (5-HTTLPR) have both increased the likelihood of adverse drug events and increased the need for higher antidepressant concentrations to obtain maximum antidepressant response. By contrast, carriers of the higher expression homozygous long allele (L/L) genotype may respond at lower concentrations. The differential role of these polymorphisms appears at early stages of treatment rather than in the final antidepressant outcome. Research findings suggest that the rs25531 SNP may influence functional expression of the L allele. Similarly, a variable number of tandem repeats in the second intron of the serotonin transporter gene may influence the expression of SLC6A4 and the implications of these variants may be influenced by aging. Two polymorphisms, rs2242466 (-182T/C) and rs5569 (1287G/A), in the norepinephrine transporter gene (SLC6A2 or NET) have been associated with antidepressant response. Studies in dopamine-related polymorphisms have focused on associations with neuroleptic-induced movement disorders. The rs1800497 variant (Taq1A) of the dopamine receptor D2 (DRD2) gene located in a noncoding 3´ region may regulate expression of D2 receptors. The rs6280 variant (Ser9Gly) of the dopamine receptor 3 (DRD3) gene may influence the binding affinity of D3 receptors as a result of serine to glycine substitution of the receptor protein. A multicenter collaborative research effort would be an effective strategy to increase sample sizes to further investigate how gene variants impact the pharmacodynamics and pharmacokinetics of psychotropic drugs in elderly persons.

Objective The authors ascertained the amount of training in psychiatric genomics that is provided in North American psychiatric residency programs.

CYP2D6 is a polymorphic gene. It has been observed to be deleted, to be duplicated and to undergo recombination events involving the CYP2D7 pseudogene and surrounding sequences. The objective of this study was to discover the genomic structure of CYP2D6 recombinants that interfere with clinical genotyping platforms that are available today.Clinical samples containing rare homozygous CYP2D6 alleles, ambiguous readouts, and those with duplication signals and two different alleles were analyzed by long-range PCR amplification of individual genes, PCR fragment analysis, allele-specific primer extension assay, and DNA sequencing to characterize alleles and genomic structure.Novel alleles, genomic structures, and the DNA sequence of these structures are described. Interestingly, in 49 of 50 DNA samples that had CYP2D6 gene duplications or multiplications where two alleles were detected, the chromosome containing the duplication or multiplication had identical tandem alleles.Several new CYP2D6 alleles and genomic structures are described which will be useful for CYP2D6 genotyping. The findings suggest that the recombination events responsible for CYP2D6 duplications and multiplications are because of mechanisms other than interchromosomal crossover during meiosis.

The influence of genetic variations in SLC6A4 (serotonin transporter gene) on citalopram treatment of depression using the Sequenced Treatment to Relieve Depression (STAR*D) sample was assessed. Of primary interest were three previously studied polymorphisms: 1) the VNTR variation of the second intron, 2) the indel promoter polymorphism (5HTTLPR or SERT), and 3) a single nucleotide polymorphism (SNP) rs25531. Additionally, SLC6A4 was resequenced to identify new SNPs for exploratory analyses. DNA from 1914 subjects in the STAR*D study were genotyped for the intron 2 VNTR region, the indel promoter polymorphism, and rs25531. Associations of these variants with remission of depressive symptoms were evaluated following citalopram treatment. In white non-Hispanic subjects, variations in the intron 2 VNTR (point-wise P = 0.041) and the indel promoter polymorphism (point-wise P = 0.039) were associated with remission following treatment with citalopram. The haplotype composed of the three candidate loci was also associated with remission, with a global p-value of 0.040 and a maximum statistic simulation p-value of 0.0031 for the S-a-12 haplotype, under a dominant model. One SNP identified through re-sequencing the SLC6A4 gene, Intron7-83-TC, showed point-wise evidence of association, which did not remain significant after correction for the number of SNPs evaluated in this exploratory analysis. No associations between these SLC6A4 variations and remission were found in the white Hispanic or black subjects. These findings suggest that multiple variations in the SLC6A4 gene are associated with remission in white non-Hispanic depressed adults treated with citalopram. The mechanism of action of these variants remains to be determined.

Psychiatric diseases that are treated with antidepressants are the leading causes of morbidity and mortality in humankind. Although antidepressants are generally well tolerated and widely available, they are not equally effective in all patients and only 35 - 45% of patients treated for depression with these drugs recover to premorbid levels of functioning. There is a need for an effective, individualized approach to antidepressant selection. One promising lead in the development of personalized medicine is the emerging field of pharmacogenomics, whereby pharmacologic agents are selected on the basis of the genotype of patients, with particular attention to drug targets and phase I- and phase II-metabolizing enzymes. This review article focuses on phase I antidepressant-metabolizing enzymes (e.g., relevant CYP enzymes). The authors first briefly review CYP nomenclature, the relevant members of the CYP superfamily and their alleles, the metabolic categories and CYP antidepressant substrates, inhibitors and inducers. The literature on the impact of CYP polymorphisms on antidepressant metabolism are also reviewed.

Background and Aims Depression and anxiety are often comorbid with alcoholism and contribute to craving and relapse. We aimed to estimate the prevalence of life-time diagnoses of major depressive disorder (MDD), substance-induced depression (SID), anxiety disorder (AnxD) and substance-induced anxiety (SIA), the effects of these comorbidities on the propensity to drink in negative emotional states (negative craving), and test whether these effects differ by sex. Design Secondary analyses of baseline data collected in a single-arm study of pharmacogenetic predictors of acamprosate response. Setting Academic medical center and affiliated community-based treatment programs in the American upper mid-west. Participants A total of 287 males and 156 females aged 18–80 years, meeting DSM-IV criteria for alcohol dependence. Measurements The primary outcome measure was ‘propensity to drink in negative emotional situations’ (determined by the Inventory of Drug Taking Situations) and the key predictors/covariates were sex and psychiatric comorbidities, including MDD, SID, AnxD and SIA (determined by Psychiatric Research Interview of Substance and Mood Disorders). Findings The prevalence of the MDD, SID and AnxD was higher in females compared with males (33.1 versus 18.4%, 44.8 versus 26.4% and 42.2 versus 27.4%, respectively; P

AIM: To investigate child and adolescent psychiatrists’ (CAPs) attention deficit hyperactivity disorder (ADHD) and oppositional defiant disorder (ODD) diagnoses and treatments in real-world clinical practice. METHODS: The medical records of 69 ADHD children (mean age = 9.5 years), newly referred to the ADHD clinic, were reviewed for their scores of parent- and teacher-reported Vanderbilt ADHD Diagnostic Rating Scales (VADRSs), CAPs’ diagnoses of ADHD and ODD, and CAPs’ treatment recommendations. Among 63 ADHD subjects who completed both parent and teacher VADRSs, we examined the agreement of the parent and teacher VADRSs. We also examined the concurrent validity of CAPs’ ODD diagnoses against the results from the VADRSs. In addition, we compared CAPs’ treatment recommendations against established ADHD and ODD guidelines. RESULTS: Among 63 ADHD subjects, the majority of the subjects (92%) met full ADHD diagnostic criteria at least in one setting (parent or teacher) on the VADRSs. Nearly half of the patients met full ADHD diagnostic criteria in two settings (parent and teacher). Relatively low agreement between the parent and teacher VADRSs were found (95%CI: -0.33 to 0.14). For 29 children who scored positive for ODD on the rating scales, CAPs confirmed the ODD diagnosis in only 12 of these case-positives, which is considered as a fair agreement between CAPs and VADRSs (95%CI: 0.10-0.53). For 27 children with no ODD diagnosis made by either CAP or VADRS, more than half of them were recommended for medication only. In contrast, where CAPs made the diagnosis of ODD, or where the parent or teacher VADRS was positive for ODD, almost all of the patients received recommendations for medication and behavior therapy. CONCLUSION: CAPs’ ADHD diagnoses have strong concurrent validity against valid rating scales, but ADHD’s most common comorbid condition - ODD - may be under-recognized.

This review article presents a summary of the recent magnetic resonance spectroscopic studies of pediatric mood disorders.Magnetic resonance imaging is a promising tool for investigating the biologic substrates of neuropsychiatric disorders without the use of ionizing radiation. This novel technique has been recently applied to pediatric patients with mood disorders. Structural, chemical, and functional abnormalities in pediatric patients with mood disorders have been reported.To date, only modest numbers of pediatric studies using magnetic resonance imaging have been conducted. Most of these studies have small sample sizes and heterogeneous subject groups. These studies have provided important information regarding the underlying neuro-circuitry and pathophysiology of these complex and disabling disorders, however.

Background: Objective methods are needed to determine when to terminate a course of electroconvulsive therapy (ECT). Heart rate variability (HRV) has proven predictive value for patients with cardiac and neurologic disorders and correlates with depression severity and treatment effects. Variable changes in HRV after ECT have been reported. Methods: Holter monitoring was performed before and after ECT in 11 patients with depression. Measures of HRV were obtained from these recordings and the relationships between HRV and treatment outcome was analyzed. Response to ECT was measured by the 24-item Hamilton Rating Scale for Depression. Results: Standard deviation of interbeat intervals (SDNN, a measure of HRV) increased in subjects who improved with ECT (P < 0.02) but not in those who became confused and agitated. Among those patients who acutely responded to ECT, SDNN increased (P < 0.05) in subjects with a sustained response but not in subjects who relapsed within 3 weeks. SDNN was significantly lower in the rapid relapse group at baseline (P < 0.05) and after ECT (P < 0.05) compared with the group with a sustained response. Conclusions: Low baseline HRV is associated with rapid relapse of depression after ECT. Both high baseline HRV and increasing HRV predict a sustained outcome. Further research is necessary to support these findings and to clarify if the serial measurement of HRV during ECT may help to determine the optimal number of treatments for each patient.

Despite the range of diverse studies that attempt to understand the comorbidity of asthma and psychiatric diagnoses, it is still not possible to provide a reliable quantitative estimate of the increased risk for anxiety and mood disorders in children with asthma. A new hypothesis for this comorbidity has evolved, however. It is likely that the stress of having a chronic illness increases the likelihood of the development of anxiety and depressive symptoms. If this were a sufficient etiologic explanation, however, increased comorbidities of psychiatric illnesses would be found in all chronic pediatric illnesses. More precise prevalence estimates of these comorbidities require the completion of large studies that use a longitudinal design and reliable and well-validated assessment instruments. The most promising direction for future research is the definition of underlying genetic vulnerabilities that reflect autonomic regulation, may contribute to the onset of some forms of asthma, and are associated with increased risk for anxiety and mood disorders.

This paper reviews recent research on adolescent smoking initiation and youth tobacco prevention and control strategies. Gender, ethnicity, family factors, and genetics are associated with smoking initiation and adolescent tobacco use. Evidence indicates that comprehensive tobacco control programs are an effective strategy for reducing adolescent smoking, and even modest gains from prevention and cessation efforts could lead to substantial reductions in the morbidity and mortality costs of smoking. Clinicians have an important role in prevention and treatment of tobacco use in adolescents, and the rate of delivery of clinical preventive services in this area should be increased. Consequently, clinicians working with adolescents should be familiar with established guidelines regarding tobacco use prevention and treatment and use general outpatient office visits as an important opportunity to prevent tobacco use.

A departmental chairman's expectations for the leader of a division of child and adolescent psychiatry vary widely. The author shares his personal experiences in this role as he describes clinical practice goals, clinical service delivery, research productivity, teaching excellence, and faculty development, as well as other administrative issues. The current shortage in senior academic leadership is discussed, as is the question of when a division of child and adolescent psychiatry should become an autonomous department.

The World Psychiatric Association’s Program on Psychiatry for the Person is founded on the World Health Organization’s recognition that health is a state of physical, mental, social, and spiritual well-being, rather than merely the absence of disease. The WHO definition of health indicates a holistic perspective that a human being cannot be reduced to a material body alone. The whole person is comprised of physical, mental, and spiritual aspects. What may not be obvious to the casual observer, however, is the fact that each of the three aspects of a person has a distinctive biological basis. Different biological systems are involved in the regulation of physical processes (e.g., sexuality, digestion, movement), algorithmic mental processes (e.g., emotional expression, language, logical reasoning), and self-aware creativity (e.g., art, science, spirituality). Measures of psychological well-being and ill-being have been shown to be associated with numerous biomarkers, adding to a growing literature indicating that the biological correlates of well-being and ill-being are mostly distinct, rather than opposites extremes of common processes. Any rigorous understanding of the biological perspective on Psychiatry for the Person must recognize the nature of these distinctive biological processes and their implications for promotion of positive health and for the prevention and treatment of ill health

The decision regarding whether to initiate treatment with an SSRI for patients with depression is a common and important question for both patients and clinicians. Multiple clinical efficacy trials have demonstrated superiority of antidepressants to placebo.[1] Recently there has been increased debate about the effectiveness of antidepressants especially among patients with mild to moderate depression.[2–4] Parker in “Antidepressants on trial: how valid is the evidence?” discusses the concerns about using pharmaceutical registration efficacy trials to answer this question.[5] He underscores the exclusion of patients with documented medical and psychiatric co-morbidity, and the method of recruiting patients as important limitations in the generalizability of these studies. He also discusses the potential impact of heterogeneity within depressed populations which include patients with more classic biologic forms of depression such as melancholia and patients with more acute and situationally related depressive symptoms. Identification of subgroups more likely to reach remission or otherwise benefit from treatment is a critical clinical question. The aim of the Pharmacogenomic Research Network Antidepressant Medication Pharmacogenomic Study (PGRN-AMPS) is to identify subgroups of patients most likely to benefit from SSRIs. The PGRN-AMPS was designed to assess clinical outcomes of patients with major depressive disorder (MDD) treated with either citalopram or escitalopram, and to investigate genetic factors associated with these outcomes. This report describes the clinical outcomes following treatment in 529 subjects and compares these treatment outcomes with those achieved in the first phase of the Sequence Treatment Alternatives to Relieve Depression Study (STAR*D). As in the STAR*D study,[6] the primary outcome measures in the PGRN-AMPS were remission defined as a Quick Inventory of Depressive Symptomatology Clinician Rated (QIDS-C16)[7] score of 5 or less and response defined as at least a 50% reduction in the QIDS-C16 score from baseline. However, unlike the STAR*D study, DNA and plasma were collected for all subjects and drug serum levels were monitored over the course of treatment. Blood drug levels were examined to assess medication adherence. The availability of DNA samples made it possible to verify self-reported gender and ethnicity which has rarely been done in depression efficacy and effectiveness studies. While STAR*D was designed to be an effectiveness trial, data from this study have been used to address pharmacogenomic questions.[8, 9] In contrast, the PGRN-AMPS was designed to be a pharmacogenomic study and was conducted by a single research team within an integrated health care system.

This literature review assessed the burden of treatment-resistant depression in the United States by compiling published data about the clinical, societal, and economic outcomes associated with failure to respond to one or more adequate trials of drug therapy.PubMed and the Tufts Cost-Effectiveness Analyses Registry were searched for English-language articles published between January 1996 and August 2013 that collected primary data about treatment-resistant depression. Two researchers independently assessed study quality and extracted data.Sixty-two articles were included (N=59,462 patients). Patients with treatment-resistant depression had 3.8±2.1 prior depressive episodes and illness duration of 4.4±3.3 years and had completed 4.7±2.7 unsuccessful drug trials involving 2.1±.3 drug classes. Response rates for treatment-resistant depression were 36%±1%. A total of 17%±6% of patients had prior suicide attempts (1.1±.2 attempts per patient). Quality-of-life scores (scale of 0-1, with 0 indicating death and 1 indicating perfect health) for patients with treatment-resistant depression were .41±.8 and .26±.8 points lower, respectively, than for patients who experienced remission or response. Annual costs for health care and lost productivity were $5,481 and $4,048 higher, respectively, for patients with treatment-resistant versus treatment-responsive depression.Treatment-resistant depression exacts a substantial toll on patients' quality of life. At current rates of 12%-20% among all depressed patients, treatment-resistant depression may present an annual added societal cost of $29-$48 billion, pushing up the total societal costs of major depression by as much as $106-$118 billion. These findings underscore the need for research on the mechanisms of depression, new therapeutic targets, existing and new treatment combinations, and tests to improve the efficacy of and adherence to treatments for treatment-resistant depression.

Problem behavior in children shows a high degree of cooccurrence, both within the domains of internalizing and externalizing behaviors and across domains. Maternal ratings of 207 same- and opposite-sex twin pairs on the Child Behavior Checklist (CBCL/4–18; Achenbach, 1991) were used to determine the etiology of these associations. In the current sample of 4- to 11-year-old children (mean age: 7.6 years) phenotypic correlations were .68 between Internalizing and Externalizing, between .41 and .66 within the internalizing scales, and between .58 and .71 within the externalizing scales. Correlations across domains on the scale level were of similar magnitude. Genetic and shared environmental correlations were generally high, with the exception of the somatic complaints scale which showed low genetic correlations with other scales. These findings of uniformly high shared etiology was seen within and across domains. For example, Attention Problems showed genetic correlations of .65 with Delinquent Behavior and .76 with Aggressive Behavior; the genetic correlations of Attention Problems with internalizing scales were .71 for Anxious/Depressed and .79 for Withdrawn; a low genetic correlation was only shown for the Somatic Complaints scale (rg = .16). Although the magnitude of shared environmental contributions was lower, the environmental correlations were close to unity, indicating that the same family environmental factors were involved in aspects of problem behavior when assessed across domains. Results for the Attention Problems scale were similar to other disruptive behavior, justifying its inclusion with the externalizing scales.

In conditions in which the retinal pigment epithelium (RPE) is dystrophic, carries a genetic mutation, or is removed physically, Muller cells undergo degenerative changes that contribute to the retinal pathology. We previously demonstrated that pigment epithelium-derived factor (PEDF), a glycoprotein secreted by the RPE cells with neuroprotective and differentiation properties, protects against photoreceptor degeneration induced by RPE removal. The purpose of the present study was to analyze the putative gliosupportive activity of PEDF on Muller cells of RPE-deprived retinas and assess whether protection of Muller cells was correlated with improved photoreceptor outer segment assembly. Eyes were dissected from Xenopus laevis tadpoles, and the RPE was removed before culturing in medium containing purified PEDF, PEDF plus anti-PEDF, or medium alone. Control eyes matured with an adherent RPE or in medium containing PEDF plus nonimmune serum. Muller cell ultrastructure was examined. Glial fibrillary acidic protein (GFAP) and glutamine synthetase were localized immunocytochemically, and the corresponding protein levels were quantified. In control retinas, Muller cells were structurally intact and formed adherens junctions with neighboring photoreceptors. In addition, they did not express GFAP, whereas glutamine synthetase expression was high. RPE removal dramatically altered the ultrastructure and biosynthetic activity of Muller cells; Muller cells failed to form adherens junctions with photoreceptors and glutamine synthetase expression was suppressed. PEDF prevented the degenerative glial response; Muller cells were ultrastructurally normal and formed junctional complexes with photoreceptors. PEDF also preserved the expression of glutamine synthetase at near-normal levels. The morphogenetic effects of PEDF were blocked by the anti-PEDF antibody. Our study documents the glioprotective effects of PEDF and suggests that maintenance of the proper Muller cell ultrastructure and expression of glutamine synthetase may be necessary to support the proper assembly of photoreceptor outer segments.

We investigated gene expression profiles of vascular endothelial growth factor (VEGF) and pigment epithelium-derived factor (PEDF) in differentiated and non-differentiated retinal pigment epithelial (RPE) cells during oxidative stress. Human RPE cells were grown in culture on laminin-coated flasks to obtain differentiated features. Cells cultured on plastic were used as non-differentiated controls. After confluence, hydrogen peroxide (H2O2) was added for 48 h, then, total RNA was extracted and used for RT-PCR and Northern blot analysis. Medium conditioned by RPE was used for ELISA, Western blotting, and in vitro angiogenesis assay. As a result, differentiated RPE cells expressed significantly higher levels of VEGF protein, as compared to their non-differentiated counterparts. The expression pattern remained consistent even after cellular exposure to H2O2. Conversely, while elevated levels of PEDF transcript and protein were seen in differentiated RPE cells, compared to non-differentiated cells, a marked decrease at both PEDF mRNA and protein levels was seen after treatment with H2O2. Moreover, this decrease in PEDF expression was dosage dependent. In in vitro angiogenesis assay, conditioned medium from differentiated human RPE cells after exposure to H2O2 showed a dramatic increase in tubular formation and migratory activity of microvascular endothelial cells. These data suggest that, in physiological conditions, a critical balance between PEDF and VEGF exists, and PEDF may counteract the angiogenic potential of VEGF. Under oxidative stress, PEDF decreases disrupting this balance. This equilibrium shift may be significant in promoting a pathological condition of RPE cells and contributing to choroidal neovascularization in age-related macular degeneration.

Pigment epithelium-derived factor (PEDF) is a protein shown to have neurotrophic activity. The purpose of this study was to determine whether PEDF is neuroprotective of retinal neurons that are exposed to transient ischemia-reperfusion.Transient retinal ischemia was produced by increasing the intraocular pressure for 45 min in albino rats eyes. Immediately after reperfusion, PEDF was injected intravitreally into the experimental eyes. Injury was evaluated morphologically and by measuring the thickness of the inner retinal layers (IRL) and by counting the number of retinal ganglion cells (RGC) in epon embedded sections.Morphologic and morphometric analysis of the thickness of the IRL and the counting of RGC demonstrated that PEDF injected immediately after reperfusion protected the eyes partially but significantly from the ischemic injury.Intravitreal injection of PEDF even after the ischemia can ameliorate retinal injury. PEDF may be useful in preventing neuronal degeneration in the inner retina resulting from ischemia.

Dysfunction of the retinal pigment epithelium (RPE), its loss, or separation from the underlying neural retina results in severe photoreceptor degeneration. Pigment epithelium-derived factor (PEDF) is a glycoprotein with reported neuroprotective and differentiation properties that is secreted in abundance by RPE cells. The "pooling" of PEDF within the interphotoreceptor matrix places this molecule in a prime physical location to affect the underlying neural retina. The purpose of this study was to analyze the morphogenetic activity of PEDF in a model of photoreceptor dysmorphogenesis induced by removal of the RPE. Eyes were dissected from embryonic Xenopus laevis, and the RPE was removed before culturing in medium containing PEDF, PEDF plus anti-PEDF antibodies, or medium alone. Control retinas were maintained with an adherent RPE. Light and electron microscopic analysis was used to examine retinal ultrastructure. Opsin was localized immunocytochemically and quantified as an index of outer segment membranous material and photoreceptor protein expression. Removal of the RPE resulted in an aberrant assembly of photoreceptor outer segments, loss of fine subcellular ultrastructure in photoreceptors, and a reduction in opsin protein levels when compared with control retinas. The addition of PEDF prevented the dysmorphic photoreceptor changes induced by RPE removal. In particular, photoreceptor ultrastructure, outer segment membrane assembly, and steady-state levels of opsin were equivalent to control conditions. Anti-PEDF antibodies completely blocked the morphogenetic activity of PEDF. These results indicate that PEDF is able to mimic the supportive role of the RPE on photoreceptors during the final stages of retinal morphogenesis.

To explore the association between specific maternal characteristics, maternal perceptions of toddler temperament, and infantile anorexia.Three groups of toddlers (aged 12-37 months) participated in this study: toddlers with infantile anorexia (n = 34), picky eaters (n = 34), and healthy eaters (n = 34). Mothers completed questionnaires that assessed their own eating attitudes, marital satisfaction, and their toddlers' temperament, and an interview that explored their attachment representations. Mothers and toddlers were videotaped during a feeding session, and toddlers were weighed and measured.Temperament ratings differentiated between infantile anorexics and healthy eaters (p.0001), with infantile anorexics receiving higher difficulty, irregularity, negativity, dependence, and unstoppable ratings. Mothers of anorexics showed greater attachment insecurity than mothers of healthy eaters (p.05), but they demonstrated neither overt eating pathology nor less marital satisfaction than the other groups. Thirty-nine percent of variance in feeding conflict was explained by toddlers' diagnoses, temperament ratings, and maternal characteristics. Twenty-one percent of variance in toddlers' weights was explained by temperament ratings and feeding conflict.Maternal characteristics and perceptions of their toddlers' temperament characteristics should be addressed in treatment for infantile anorexia.

This article characterizes the academic, administrative, clinical service, and fiscal characteristics of departments of psychiatry in traditional children's hospitals to determine the characteristics of fiscally successful programs. A survey of chairs of psychiatry from short-term general children's hospitals was conducted based on 38 questions addressing the descriptive characteristics of their respective departments. The characteristics of psychiatry programs identified as fiscally successful were compared to those of programs that required subsidy. Nine of 45 eligible children's hospitals (20%) did not have a department or section of psychiatry, and surveys were returned by 35 of 36 department chairs (97% response). Considerable variation exists in the academic, administrative, clinical services, and fiscal characteristics of programs, although over half are operating at a deficit. Fiscal success was associated with availability of inpatient and intermediate levels of psychiatric care, better integration of the psychiatry program within the children's hospital, and adequate fiscal information being provided to the psychiatry chair. Additional research regarding the potential of psychiatric services to generate clinical success and cost savings is warranted. Pediatric health care professionals and third-party payers should be educated regarding the relevance of psychiatric services within children's hospitals and in physically ill children.