TSPAN5, ERICH3 and selective serotonin reuptake inhibitors in major depressive disorder: pharmacometabolomics-informed pharmacogenomics.

Millions of patients suffer from major depressive disorder (MDD), but many do not respond to selective serotonin reuptake inhibitor (SSRI) therapy. We used a pharmacometabolomics-informed pharmacogenomics research strategy to identify genes associated with metabolites that were related to SSRI response. Specifically, 306 MDD patients were treated with citalopram or escitalopram and blood was drawn at baseline, 4 and 8 weeks for blood drug levels, genome-wide single nucleotide polymorphism (SNP) genotyping and metabolomic analyses. SSRI treatment decreased plasma serotonin concentrations (P<0.0001). Baseline and plasma serotonin concentration changes were associated with clinical outcomes (P<0.05). Therefore, baseline and serotonin concentration changes were used as phenotypes for genome-wide association studies (GWAS). GWAS for baseline plasma serotonin concentrations revealed a genome-wide significant (P=7.84E-09) SNP cluster on chromosome four 5' of TSPAN5 and a cluster across ERICH3 on chromosome one (P=9.28E-08) that were also observed during GWAS for change in serotonin at 4 (P=5.6E-08 and P=7.54E-07, respectively) and 8 weeks (P=1.25E-06 and P=3.99E-07, respectively). The SNPs on chromosome four were expression quantitative trait loci for TSPAN5. Knockdown (KD) and overexpression (OE) of TSPAN5 in a neuroblastoma cell line significantly altered the expression of serotonin pathway genes (TPH1, TPH2, DDC and MAOA). Chromosome one SNPs included two ERICH3 nonsynonymous SNPs that resulted in accelerated proteasome-mediated degradation. In addition, ERICH3 and TSPAN5 KD and OE altered media serotonin concentrations. Application of a pharmacometabolomics-informed pharmacogenomic research strategy, followed by functional validation, indicated that TSPAN5 and ERICH3 are associated with plasma serotonin concentrations and may have a role in SSRI treatment outcomes.

The International SSRI Pharmacogenomics Consortium (ISPC): a genome-wide association study of antidepressant treatment response.

Response to treatment with selective serotonin reuptake inhibitors (SSRIs) varies considerably between patients. The International SSRI Pharmacogenomics Consortium (ISPC) was formed with the primary goal of identifying genetic variation that may contribute to response to SSRI treatment of major depressive disorder. A genome-wide association study of 4-week treatment outcomes, measured using the 17-item Hamilton Rating Scale for Depression (HRSD-17), was performed using data from 865 subjects from seven sites. The primary outcomes were percent change in HRSD-17 score and response, defined as at least 50% reduction in HRSD-17. Data from two prior studies, the Pharmacogenomics Research Network Antidepressant Medication Pharmacogenomics Study (PGRN-AMPS) and the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, were used for replication, and a meta-analysis of the three studies was performed (N=2394). Although many top association signals in the ISPC analysis map to interesting candidate genes, none were significant at the genome-wide level and the associations were not replicated using PGRN-AMPS and STAR*D data. The top association result in the meta-analysis of response represents SNPs 5' upstream of the neuregulin-1 gene, NRG1 (P = 1.20E - 06). NRG1 is involved in many aspects of brain development, including neuronal maturation and variations in this gene have been shown to be associated with increased risk for mental disorders, particularly schizophrenia. Replication and functional studies of these findings are warranted.

Clinical validity: Combinatorial pharmacogenomics predicts antidepressant responses and healthcare utilizations better than single gene phenotypes.

In four previous studies, a combinatorial multigene pharmacogenomic test (GeneSight) predicted those patients whose antidepressant treatment for major depressive disorder resulted in poorer efficacy and increased health-care resource utilizations. Here, we extended the analysis of clinical validity to the combined data from these studies. We also compared the outcome predictions of the combinatorial use of allelic variations in genes for four cytochrome P450 (CYP) enzymes (CYP2D6, CYP2C19, CYP2C9 and CYP1A2), the serotonin transporter (SLC6A4) and serotonin 2A receptor (HTR2A) with the outcome predictions for the very same subjects using traditional, single-gene analysis. Depression scores were measured at baseline and 8-10 weeks later for the 119 fully blinded subjects who received treatment as usual (TAU) with antidepressant standard of care, without the benefit of pharmacogenomic medication guidance. For another 96 TAU subjects, health-care utilizations were recorded in a 1-year, retrospective chart review. All subjects were genotyped after the clinical study period, and phenotype subgroups were created among those who had been prescribed a GeneSight panel medication that is a substrate for either CYP enzyme or serotonin effector protein. On the basis of medications prescribed for each subject at baseline, the combinatorial pharmacogenomic (CPGx™) GeneSight method categorized each subject into either a green ('use as directed'), yellow ('use with caution') or red category ('use with increased caution and with more frequent monitoring') phenotype, whereas the single-gene method categorized the same subjects with the traditional phenotype (for example, poor, intermediate, extensive or ultrarapid CYP metabolizer). The GeneSight combinatorial categorization approach discriminated and predicted poorer outcomes for red category patients prescribed medications metabolized by CYP2D6, CYP2C19 and CYP1A2 (P=0.0034, P=0.04 and P=0.03, respectively), whereas the single-gene phenotypes failed to discriminate patient outcomes. The GeneSight CPGx process also discriminated health-care utilization and disability claims for these same three CYP-defined medication subgroups. The CYP2C19 phenotype was the only single-gene approach to predict health-care outcomes. Multigenic combinatorial testing discriminates and predicts the poorer antidepressant outcomes and greater health-care utilizations by depressed subjects better than do phenotypes derived from single genes. This clinical validity is likely to contribute to the clinical utility reported for combinatorial pharmacogenomic decision support.

Genetic markers associated with abstinence length in alcohol-dependent subjects treated with acamprosate.

Acamprosate supports abstinence in some alcohol-dependent subjects, yet predictors of response are unknown. To identify response biomarkers, we investigated associations of abstinence length with polymorphisms in candidate genes in glycine and glutamate neurotransmission pathways and genes previously implicated in acamprosate response. Association analyses were conducted in the discovery sample of 225 alcohol-dependent subjects treated with acamprosate for 3 months in community-based treatment programs in the United States. Data from 110 alcohol-dependent males treated with acamprosate in the study PREDICT were used for replication of the top association findings. Statistical models were adjusted for relevant covariates, including recruitment site and baseline clinical variables associated with response. In the discovery sample, shorter abstinence was associated with increased intensity of alcohol craving and lower number of days between the last drink and initiation of acamprosate treatment. After adjustment for covariates, length of abstinence was associated with the GRIN2B rs2058878 (P=4.6 × 10(-5)). In the replication sample, shorter abstinence was associated with increased craving, increased depressive mood score and higher alcohol consumption. Association of abstinence length with GRIN2B rs2058878 was marginally significant (P=0.0675); as in the discovery sample, the minor A allele was associated with longer abstinence. Furthermore, rs2300272, which is in strong linkage disequilibrium with rs2058878, was also associated with abstinence length (P=0.049). This is the first report of a replicated association of genetic markers with the length of abstinence in acamprosate-treated alcoholics. Investigation of the underlying mechanisms of this association and its usefulness for individualized treatment selection should follow.

Using a pharmacogenomic algorithm to guide the treatment of depression.

The objective of this study was to evaluate the potential benefit of utilizing a pharmacogenomic testing report to guide the selection and dosing of psychotropic medications in an outpatient psychiatric practice. The non-randomized, open label, prospective cohort study was conducted from September 2009 to July 2010. In the first cohort, depressed patients were treated without the benefit of pharmacogenomic testing (the unguided group). A DNA sample was obtained from patients in the unguided group, but the results were not shared with either the physicians or patients until the end of the 8-week study period. In the second cohort (the guided group), testing results were provided at the beginning of the 8-week treatment period. Depression ratings were collected at baseline and after 2 weeks, 4 weeks and 8 weeks of treatment using the Quick Inventory of Depressive Symptomatology, Clinician Rated (QIDS-C16) and the 17-item Hamilton Rating Scale for Depression (HAM-D17). Clinician and patient satisfaction was also assessed. The reduction in depressive symptoms achieved within the guided treatment group was greater than the reduction of depressive symptoms in the unguided treatment group using either the QIDS-C16 (P=0.002) or HAM-D17 (P=0.04). We concluded that a rapidly available pharmacogenomic interpretive report provided clinical guidance that was associated with improved clinical outcomes for depressed patients treated in an outpatient psychiatric clinic setting.

A lipoxygenase inhibitor in breast cancer brain metastases.

The complication of multiple brain metastases in breast cancer patients is a life threatening condition with limited success following standard therapies. The arachidonate lipoxygenase pathway appears to play a role in brain tumor growth as well as inhibition of apoptosis in in-vitro studies. The down regulation of these arachidonate lipoxygenase growth stimulating products therefore appeared to be a worthwhile consideration for testing in brain metastases not responding to standard therapy. Boswellia serrata, a lipoxygenase inhibitor was applied for this inhibition. Multiple brain metastases were successfully reversed using this method in a breast cancer patient who had not shown improvement after standard therapy. The results suggest a potential new area of therapy for breast cancer patients with brain metastases that may be useful as an adjuvant to our standard therapy.

New polyethylene glycol laxative for treatment of constipation in adults: a randomized, double-blind, placebo-controlled study.

BACKGROUND: This study evaluated the safety and effectiveness of a new polyethylene glycol (PEG) laxative (MiraLax, Braintree Laboratories Inc, Braintree, Mass) in 23 patients reporting a history of constipation. METHODS: After a 7-day placebo control period, patients were randomized into a double crossover trial of placebo versus 17 g of PEG daily for 4 days. Patient maintained a stool diary. RESULTS: Daily ingestion of a 17 g dose of PEG increased mean daily bowel movement frequency to once per day by the last 7 days of the 14-day treatment period. This was a statistically significant improvement over placebo, which provided about 1 bowel movement every 2 days during the last week of therapy. Patient diary ratings of related subjective symptoms were improved with PEG treatment over placebo. Both investigator and patients rated PEG therapy superior to placebo. No clinically significant changes in blood chemistry, complete blood count (CBC), or urinalysis were observed. CONCLUSIONS: Daily therapy with 17 g of PEG laxative for 14 days resulted in a significant improvement in bowel movement frequency in constipated patients relative to placebo by the second week of treatment.

Detectable blood alcohol after a motor vehicle crash and screening for alcohol abuse/dependence.

OBJECTIVE: To determine the percentage of patients hospitalized after an alcohol-related motor vehicle crash (MVC) who underwent a screening evaluation for alcohol abuse/dependence and had a diagnosis of alcohol abuse/dependence. PATIENTS AND METHODS: Medical and emergency trauma records were reviewed retrospectively for 1994 through 1996 to identify patients who were hospitalized as a result of being involved in an MVC with any detected blood alcohol at the time of admission to a large midwestern Level I trauma center. The primary outcome measure was the performance of alcohol abuse/dependence screening by a psychiatrist or a chemical dependency counselor. A univariate analysis was performed to identify factors associated with the performance of alcohol abuse/dependence screening. The Fisher exact test and the 2-sample rank sum test were used in the analyses. RESULTS: Of the 294 study patients, 78 (26.5%) underwent a screening evaluation for alcohol abuse/dependence by a psychiatrist or a chemical dependency counselor during hospitalization, and 69 (88%) of the 78 patients screened had a diagnosis of alcohol abuse/dependence. Factors associated with the performance of alcohol abuse/dependence evaluation included a known prior history of alcohol abuse, suspicion of alcohol consumption documented by emergency department personnel, higher blood alcohol level at admission, and longer length of hospitalization (all P < .001). CONCLUSION: While the high rate of alcohol abuse/dependence may be explained partially by distinguishing factors in those screened, these findings suggest that routine alcohol abuse/dependence screening of persons presenting with a detectable blood alcohol level following an MVC may identify patients who would benefit from a chemical dependency intervention.

Dispersion-insensitive measurement of thickness and group refractive index by low-coherence interferometry.

We describe a low-coherence interferometric technique for simultaneous measurement of geometric thickness and group refractive index of highly dispersive samples. The technique is immune to the dispersion-induced asymmetry of the interferograms, thus overcoming limitations associated with some other low-coherence approaches to this simultaneous measurement. We use the experimental configuration of a tandem interferometer, with the samples to be characterized placed in an air gap in one arm of the measurement interferometer. Unambiguous, dispersion-insensitive measurements of critical group-delay imbalances in the measurement interferometer are determined from the optical frequency dependence of interferogram phases, by means of dispersive Fourier transform spectrometry. Sample thickness and group refractive index are calculated from these group delays. A thickness measurement precision of 0.2 microm and group index measurement accuracy of 5 parts in 10(5) across a wavelength range of 150 nm have been achieved for BK7 and fused-silica glass samples in the thickness range 2000 to 6000 microm.

The successful treatment of autoimmune hepatitis with 6-mercaptopurine after failure with azathioprine.

Although the treatment of choice for autoimmune hepatitis is glucocorticoids, their side effects make long-term use undesirable. Therefore, other immunosuppressive agents have been used to replace glucocorticoids in the long-term treatment of autoimmune hepatitis, including azathioprine, a purine analogue. It is derived from 6-mercaptopurine, and these two drugs are often used interchangeably. However, these drugs have different toxicity profiles and may have clinically relevant differences in immunosuppressive activity in individual patients. We report 3 patients with autoimmune hepatitis who either could not tolerate or failed to improve on azathioprine but responded well to 6-mercaptopurine.

Combined temperature and strain measurement with a dispersive optical fiber Fourier-transform spectrometer.

We report simultaneous measurement of strain and temperature in single-mode optical fiber by broadband interferometry. A Mach-Zehnder interferometer, illuminated by a xenon-arc lamp, has a sensing element in one arm. Scanning an air path generates interferograms that are calibrated by a monochromatic reference interferogram. Values of group delay and dispersion, obtained from the phase of the fast Fourier transform of the sampled interferogram, give strain and temperature through a well-conditioned matrix transformation without phase ambiguity. We obtained measurement ranges and resolutions of 1500 +/- 12 microstrain and 25.0 +/- 0.4 K using a 0.8-m sensing element.

The definition of alcoholism. The Joint Committee of the National Council on Alcoholism and Drug Dependence and the American Society of Addiction Medicine to Study the Definition and Criteria for the Diagnosis of Alcoholism.

To establish a more precise use of the term alcoholism, a 23-member multidisciplinary committee of the National Council on Alcoholism and Drug Dependence and the American Society of Addiction Medicine conducted a 2-year study of the definition of alcoholism in the light of current concepts. The goals of the committee were to create by consensus a revised definition that is (1) scientifically valid, (2) clinically useful, and (3) understandable by the general public. Therefore, the committee agreed to define alcoholism as a primary, chronic disease with genetic, psychosocial, and environmental factors influencing its development and manifestations. The disease is often progressive and fatal. It is characterized by impaired control over drinking, preoccupation with the drug alcohol, use of alcohol despite adverse consequences, and distortions in thinking, most notably denial. Each of these symptoms may be continuous or periodic.

Alcoholism and orthotopic liver transplantation.

KIE: The authors, who are affiliated with the National Council on Alcoholism, reject policies that preclude consideration of liver transplantation based solely on a diagnosis of alcoholism. They urge public and private third party payers to cooperate with clinicians experienced in the field of alcoholism in the preparation of guidelines, based on careful research, that avoid arbitrary abstinence requirements and take into account the successes of treatment for alcoholism. The authors assert that a "dangerous precedent is set when decisions regarding either the indications for a procedure or criteria for funding of such becomes based on social rather than clearly documented, objectively established medical criteria corroborated by sound data."^ieng

Risk-taking behavior, substance abuse disorders, and the acquired immune deficiency syndrome.

The Acquired Immune Deficiency Syndrome (AIDS) has rapidly emerged as a public health crisis of unusual proportion. Despite the attention given to the association of AIDS and parenteral substance use, the relationship between AIDS and other aspects of substance use disorders such as risk taking, disinhibition and lack of self care has not been emphasized. In vitro and in vivo evidence of immune suppression as a result of substance abuse, coupled with behavioral disinhibition and co-existent psychiatric problems make the relationship between these two public health problems a likely area of concern. Substance abuse, increased risk taking and self destructiveness are co-factors involved in the transmission of AIDS which need to be studied epidemiologically. The authors address the relationship between the addictions and disinhibition, suicidal behavior, and the clinical and therapeutic needs of patients, their families and staff.

The acquired immune deficiency syndrome (AIDS) and suicidal behavior in alcohol-dependent homosexual men.

Three alcohol-dependent homosexual men with suicidal ideation and behavior consciously attempted to contract the acquired immune deficiency syndrome (AIDS) as a means of committing suicide. The authors briefly examine the interrelationship among alcoholism and substance abuse, homosexuality, suicidal behavior, and AIDS; implications for the substance abuse treatment setting are noted. Early diagnosis and treatment of depression and substance abuse in homosexual men or parenteral drug abusers may prevent the spread of AIDS and reduce hidden suicidal potential.

Toxicity, tumor promotion, and carcinogenesis in relation to excessive dosage.

Excessive dosage of many toxic compounds leads to a response by those exposed cells in the form of toxic hyperplasia. This toxicity often is a result of oxidation and peroxidation products that affect multiple sites of critical importance in the cell from the membrane of DNA itself. Some of these products are both mutagenic and carcinogenic and can affect key enzymes of defense and proliferation. Chronic toxicity of this type can deplete or inactivate endogenous defense systems that would normally prevent the formation of these toxic products. Subtoxic doses will not significantly compromise cellular defense systems and are far less likely to induce the critical events associated with hyperplasia, tumor promotion, and the expression of a "carcinogenic" effect. The many new discoveries in oxidation and peroxidation toxicity open up a greater awareness of the potential problems of interpretation associated with excessive dosage in evaluation of compounds for carcinogenicity.