Association Study of Genotype by Depressive Response during Tryptophan Depletion in Subjects Recovered from Major Depression.

PURPOSE: The brief and reversible mood response to acute tryptophan (TRP) depletion (ATD) is being studied as a trait marker in subjects considered at risk for major depression (MD). PROCEDURES: ATD was administered to 64 subjects (54 European-Americans, and10 from other races) with personal and family history of MD. They were in remission and had been medication-free for at least three months. Subjects received an active and sham condition in a random assignment, double-blind crossover design. They were genotyped for serotonin-related candidate genes, and mood response was quantified with the Hamilton Depression Rating Scale (HDRS). Data were analyzed using Poisson regression with repeated measures and latent trajectory models. RESULTS: Compared to the sham control, active ATD caused modest depressive changes showing significant main effects of test condition (χ2=5.14, df=1, p=0.023) and time (χ2=12.22, df=3, p=0.007), but no significant interaction of time and test condition. Latent trajectory analysis revealed two groups, identified as depletion responders and non-responders. Those with the HTR2A rs6313 CC genotype had significantly higher HDRS scores during ATD (χ2=11.72, df=1, p=.0006). CONCLUSIONS AND MESSAGE: ATD may help the identification of biological subtypes of MD. These data are consistent with imaging reports implicating 5-HT2A receptor function in ATD phenotypes.

Pilot Study of a Computer-Based Parental Questionnaire and Visual Profile of Obesity Risk in Healthy Preschoolers.

PURPOSE: This group field-tested a computer-based, parental questionnaire entitled the Childhood Obesity Risk Questionnaire 2-5 (CORQ 2-5) designed to assess obesity risk in healthy preschoolers. COR 2-5 generates a profile of seven obesity risk factors. RESULTS: Field studies provided good internal reliability data and evidence of discriminant validity for the CORQ 2-5. Pediatric nurse clinicians found the CORQ 2-5 profile to be clinically relevant. CONCLUSION: The CORQ 2-5 is a promising measure of obesity risk in preschoolers who attend community-based health centers for their wellchild visits and who are not yet obese. CORQ 2-5 is intended to guide provider-parental obesity risk discussions.

The development and effectiveness of a health information website designed to improve parents' self-efficacy in managing risk for obesity in preschoolers.

PURPOSE: To evaluate the effects of web-based information on parental self-efficacy in managing obesity risk in preschoolers. DESIGN AND METHODS: The project included a literature review and the development and field testing of an information website that presented information on how to manage nine obesity risk factors for childhood obesity. RESULTS: Parents stated that they had no problems using the website, and 69% reported improved self-efficacy on at least two risk factors. PRACTICE IMPLICATIONS: Many parents access the Internet to obtain health information. A website that offers practical information on managing childhood obesity risk factors is a valuable resource for obesity prevention efforts.

The implications of genomics on the nursing care of adults with neuropsychiatric conditions.

PURPOSE: Neuropsychiatric disorders contribute substantially to disease burden and quality of life across the lifespan and the globe. The purpose of this article is to review the state of the science regarding genomic contributions to selected common neuropsychiatric conditions and to examine the consequent immediate and future implications for nursing practice and research. ORGANIZING CONSTRUCT: Our work is guided by an ecological model that recognizes that common diseases are complex or multifactorial, meaning that multiple genomic and environmental factors contribute to their etiology. METHODS: A review of the literature was conducted to determine the state of the science in relationship to the genomic contributions to selected neuropsychiatric disorders. FINDINGS: Neuropsychiatric conditions are genomically heterogeneous, both within a single disorder and across groups of disorders. While recent genomic research yields clinically validated and useful information for a small subset of persons (e.g., predictive genetic testing for Huntington disease and early-onset Alzheimer disease), broad clinical application of genetic information is not yet available. In addition, the implications of genomics for the development and targeting of nonpharmacologic treatment strategies is largely unexplored. CONCLUSIONS: Further research is needed to expand knowledge beyond genomic risk for the presence of disease to knowledge about the genomic risk for symptoms, symptom burden, and tailored symptom management interventions. CLINICAL RELEVANCE: Knowledge about the genomic influences on neuropsychiatric conditions suggests important implications for practicing nurses in the identification of persons at risk, provision of follow-up support, and in the administration of medications.

Functional SNPs in genes encoding the 5-HT2A receptor modify the affinity and potency of several atypical antipsychotic drugs.

Atypical antipsychotic drugs (AADs) are the standard treatment for both the acute and long-term management of schizophrenia and an augmentation to mood stabilizers for bipolar disorder (BD). Yet many individuals who take AADs do not fully respond to them, while others experience side effects that include weight gain and metabolic disorder. This in vitro pharmacogenetic study examined whether allelic variants in the 5-hydroxytryptamine (HT)(2A) receptor alter the in vitro pharmacology of six AADs (clozapine, olanzapine, risperidone, quetiapine, ziprasidone, and aripiprazole). We selected 4 functional single-nucleotide polymorphisms (SNPs) for investigation (Thr25Asn, Ile197Val, Ala447Val, and His452Tyr), conducted site-directed mutagenesis studies to induce variants into human HEK-293 cell lines, and screened allelic variants for their effects on 5-HT( 2A) receptors in the cell lines. We conducted numerous binding assays and fluorescence-based assay system (FLEX station) experiments using the six AADs. Our results indicated that three polymorphic 5-HT(2A) receptors (Ile197Val, Ala447Val, and His452Tyr) exhibited statistically significant, though modest, changes in atypical antipsychotic affinity. In addition, three polymorphic receptors (Thr25Asn, Ile197Val, and His452Try) altered AAD potency. Our findings support in vivo evidence that functional SNPs in genes encoding neuroreceptor drug targets could explain interindividual differences in AAD drug response and tolerability. We suggest that more in vivo pharmacogenetic studies of well-characterized patients who are prescribed AADs be indicated. Future pharmacogenetic studies of well-characterized patients will likely involve tagging SNPs and the use of haplotypes related to other genes encoding neuroreceptor drug targets.

Incorporating evidence from pharmacologic and pharmacogenetic studies of atypical antipsychotic drugs into advanced psychiatric nursing practice.

PURPOSE: To present a conceptual framework for incorporating pharmacologic findings and pharmacogenetic evidence related to atypical antipsychotic drugs (AADs) into advanced psychiatric nursing practice. CONCLUSIONS: Three evidence domains lend important information about differential AAD response. These include the pharmacology of AADs, the molecular genetics of metabolizing enzymes, and the molecular genetics of neurotransmitter receptor drug targets. PRACTICE IMPLICATIONS: These evidence domains can be incorporated into nursing practice decisions related to medication planning, patient and family education, and medication monitoring processes. The central focus of the framework is patient outcomes, which include medication adherence, tolerability of the AADs, and demonstrated clinical effectiveness.

A comparison of the life goals program and treatment as usual for individuals with bipolar disorder.

OBJECTIVE: This randomized controlled study of 164 outpatients with bipolar disorder in a community mental health center who received standardized psychoeducation (Life Goals Program [LGP]) or treatment as usual sought to determine whether there were differences between the groups in medication adherence attitudes and behaviors. METHODS: Patients were randomly assigned to treatment as usual (N=80) or treatment as usual plus LGP (N=84) and were assessed at baseline and at the three-, six-, and 12-month follow-up. Primary outcomes were change in score from baseline on the Drug Attitude Inventory (DAI) and on self-reported treatment adherence behaviors (SRTAB). RESULTS: At baseline, there were no significant differences between the two groups. Slightly less than half (N=41, 49%) of the LGP group participated in most or all (four to six) LGP sessions, 14% (N=12) participated in one to three sessions, and 37% (N=31) did not participate in any sessions. At the 12-month follow-up there was improvement among all patients, with no significant differences between the two groups, in DAI scores, SRTAB, symptoms, psychopathology, and functional status. Greater depressive severity at baseline was associated with more negative attitudes toward treatment over time, although this finding was not significant (p=.056). Secondary analysis of persons in the LGP group found that compared with those who did not go to any LGP sessions, those with partial or full participation in LGP sessions had improved attitudes toward medication at the three- and six-month follow-up, but no difference was found between the three LGP subgroups by the 12-month follow-up. CONCLUSIONS: There were no differences between two groups in treatment attitudes at the 12-month follow-up. Low attendance rates mitigated effects on primary outcomes. Effects of LGP may become lost over time without ongoing intervention, and individuals with depression may have reduced response to LGP.

The highly efficacious actions of N-desmethylclozapine at muscarinic receptors are unique and not a common property of either typical or atypical antipsychotic drugs: is M1 agonism a pre-requisite for mimicking clozapine's actions?

RATIONALE: Recent studies have suggested that the salutary actions of clozapine in schizophrenia may be due to selective activation of M(1) muscarinic receptors by clozapine and/or its major active metabolite N-desmethylclozapine. OBJECTIVE: We systematically tested this hypothesis by screening a large number of psychoactive compounds, including many atypical antipsychotic drugs, for agonist activity at cloned, human M(1), M(3) and M(5) muscarinic receptors. RESULTS: Only three of the 14 atypical antipsychotic drugs we tested were found to possess partial agonist actions at M(1) muscarinic receptors (fluperlapine, JL13, clozapine). A few additional miscellaneous compounds had a modest degree of M(1) agonist actions. Only carbachol and N-desmethylclozapine had appreciable M(3) muscarinic agonism at M(3) muscarinic receptors, although several were M(5) partial agonists including MK-212, N-desmethylclozapine and xanomeline. CONCLUSION: Although M(1) muscarinic receptor-selective partial agonists have shown promise in some preclinical antipsychotic drug models, these studies indicate that it is unlikely that the salutary actions of clozapine and similar atypical antipsychotic drugs are mediated solely by M(1) muscarinic receptor activation. It is possible, however, that the M(1) agonism of N-desmethylclozapine contributes to the uniquely beneficial actions of clozapine. Thus, these results are consistent with the notion that a balanced degree of activity at multiple biogenic amine receptors, including M(1) muscarinic agonism, is responsible for the uniquely beneficial actions of clozapine.

Aripiprazole: a novel atypical antipsychotic drug with a uniquely robust pharmacology.

Aripiprazole (Abilify) is an atypical antipsychotic drug that has been recently introduced for clinical use in the treatment of schizophrenia. Aripiprazole has a unique pharmacologic profile that includes partial agonism at several G-protein coupled receptors (GPCRs) [especially dopamine (D2) and 5-HT1A] and antagonistic action at others (especially 5-HT2A). Clinical trials indicate that aripiprazole is effective in treating the positive and negative symptoms of schizophrenia. In short-term studies rapid onset of action (within one week) has been demonstrated. Preliminary data indicate that aripiprazole may also be effective in the treatment of manic symptoms of bipolar disorder. At recommended doses, aripiprazole appears to be safe and well tolerated in most adult patients with schizophrenia and schizoaffective disorder. There is only limited information available on the use of aripiprazole in children and adolescents, and pilot data suggest that a revised dosing strategy, based on weight, is indicated in this population. In the long-term studies, the use of aripiprazole was associated with continued efficacy, good compliance and increased time-to-relapse. Aripiprazole represents the first functionally selective atypical antipsychotic drug.

Impact of bipolar disorder on a U.S. community sample.

BACKGROUND: Bipolar disorder is a chronic psychiatric illness characterized by depression and at least 1 manic or hypomanic episode during the lifetime of the illness. Bipolar symptoms have been associated with significant functional impairment. We conducted a study to determine the psychosocial impact of bipolar disorder in a U.S. community sample. METHOD: 3059 subjects were selected from a large epidemiologic study of bipolar prevalence that used the Mood Disorder Questionnaire (MDQ) to screen for bipolar I and II disorder. Subjects were surveyed from April 24, 2001, to August 6, 2001, using the Sheehan Disability Scale and the Social Adjustment Scale-Self Report. Comorbid disease data were also collected. RESULTS: Of the 3059 subjects surveyed, 2450 (80%) returned completed surveys: 1167 (48%) subjects screened positive for bipolar disorder based on MDQ scores; 1283 (52%) screened negative. MDQ-positive subjects reported significantly (p <.0001) more difficulties with work-related performance, social/leisure activities, and social/family interactions compared with MDQ-negative subjects. Younger subjects, aged 18 to 34 years, reported significantly (p =.003) more symptom days than did older MDQ-positive subjects. MDQ-positive women reported more disruption in social and family life, while MDQ-positive men reported being jailed, arrested, and convicted for crimes. Anxiety (30% vs. 6%), panic attacks (18% vs. 4%), migraine (24% vs. 11%), asthma (17% vs. 10%), and allergies (42% vs. 29%) were significantly (p <.05) more common in MDQ-positive versus MDQ-negative subjects. CONCLUSION: Bipolar disorder, as identified in a community sample using the Mood Disorder Questionnaire, was significantly associated with negative impact on the performance of work-related, leisure, and interpersonal activities.

Screening for bipolar disorder in the community.

BACKGROUND: Our goal was to estimate the rate of positive screens for bipolar I and bipolar II disorders in the general population of the United States. METHOD: The Mood Disorder Questionnaire (MDQ), a validated screening instrument for bipolar I and II disorders, was sent to a sample of 127,800 people selected to represent the U.S. adult population by demographic variables. 85,358 subjects (66.8% response rate) that were 18 years of age or above returned the survey and had usable data. Of the nonrespondents, 3404 subjects matched demographically to the 2000 U.S. Census data completed a telephone interview to estimate nonresponse bias. RESULTS: The overall positive screen rate for bipolar I and II disorders, weighted to match the 2000 U.S. Census demographics, was 3.4%. When adjusted for the nonresponse bias, the rate rose to 3.7%. Only 19.8% of the individuals with positive screens for bipolar I or II disorders reported that they had previously received a diagnosis of bipolar disorder from a physician, whereas 31.2% reported receiving a diagnosis of unipolar depression. An additional 49.0% reported receiving no diagnosis of either bipolar disorder or unipolar depression. Positive screens were more frequent in young adults and low income households. The rates of migraine, allergies, asthma, and alcohol and drug abuse were substantially higher among those with positive screens. CONCLUSION: The positive MDQ screen rate of 3.7% suggests that nearly 4% of American adults may suffer from bipolar I and II disorders. Young adults and individuals with lower income are at greater risk for this largely underdiagnosed disorder.