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ABSTRACT: Persons with bipolar disorder face excess risk of cardiovascular disease, although the biobehavioral mechanisms and time course are unclear. We measured vascular stiffness in a cross-sectional sample of participants with bipolar disorder and compared results to published normative data to assess time-course and relationship to behavioral risk factors.
62 individuals with bipolar disorder (33±6.7years; 64% female) underwent non-invasive assessment of arterial stiffness through arterial applanation tonometry. Lifetime tobacco exposure was estimated on clinical interview. Physical activity was assessed using the long-version of the International Physical Activity Questionnaire (IPAQ). A food frequency questionnaire was used to compute Alternate Healthy Eating Index (AHEI), a measure of overall dietary quality. Medication histories were systematically abstracted from pharmacy records.
Participants over the age of 32 (median split) had greater arterial stiffness than expected from age-based population norms for pulse wave velocity (PWV) (7.6 vs. 7.0m/s, p=.02) and estimated aortic augmentation pressure (AIx) (14.2 vs. 8.2%, p=.0002). The younger portion of the sample did not differ from population norms on these measures (PWV 6.3 vs. 6.4m/s, p=.45 and AIx 7.6 vs. 7.4%, p=.60). In the older half of the sample, physical activity was inversely associated with AIx and poorer diet marginally associated with PWV. These findings were independent of body mass index (BMI), which was strongly related to arterial stiffness.
Risk for vascular disease may be acquired over the long-term course of affective illness. This risk appears to reflect maladaptive health behaviors, which may be amenable to intervention.
Journal of psychosomatic research 09/2012; 73(3):175-9. · 2.91 Impact Factor
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Richard S E Keefe,
Sophia Vinogradov,
Alice Medalia,
Peter F Buckley,
Stanley N Caroff,
Deepak C D'Souza,
Phillip D Harvey,
Karen A Graham,
Robert M Hamer,
Stephen M Marder, Del D Miller,
Stephen J Olson,
Jayendra K Patel,
Dawn Velligan,
Trina M Walker,
Adam J Haim,
T Scott Stroup
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ABSTRACT: The true benefit of pharmacologic intervention to improve cognition in schizophrenia may not be evident without regular cognitive enrichment. Clinical trials assessing the neurocognitive effects of new medications may require engagement in cognitive remediation exercises to stimulate the benefit potential. However, the feasibility of large-scale multisite studies using cognitive remediation at clinical trials sites has not been established.
53 adult patients with DSM-IV schizophrenia from 9 university-affiliated sites were randomized to a cognitive remediation condition that included the Posit Science Brain Fitness auditory training program with weekly Neuropsychological and Educational Approach to Remediation (NEAR) "bridging groups" or a control condition of computer games and weekly healthy lifestyles groups. Patients were expected to complete 3 to 5 one-hour sessions weekly for 40 sessions or 12 weeks, whichever came first. The primary outcomes were feasibility results as measured by rate of enrollment, retention, and completion rate of primary outcome measures. The study was conducted from July 2009 through January 2010.
During a 3-month enrollment period, 53 (of a projected 54) patients were enrolled, and 41 (77%) met criteria for study completion. Thirty-one patients completed all 40 sessions, and all patients completed all primary outcome measures. Preliminary efficacy results indicated that, after 20 sessions, patients in the cognitive remediation condition demonstrated mean MATRICS Consensus Cognitive Battery composite score improvements that were 3.7 (95% CI, 0.05-7.34) T-score points greater than in patients in the computer-games control group (F(1,46) = 4.16, P = .047). At the end of treatment, a trend favoring cognitive remediation was not statistically significant (F(1,47) = 2.26, P = .14).
Multisite clinical trials of cognitive remediation using the Posit Science Brain Fitness auditory training program with the NEAR method of weekly bridging groups at traditional clinical sites appear to be feasible.
ClinicalTrials.gov identifier: NCT00930150.
The Journal of Clinical Psychiatry 05/2012; 73(7):1016-22. · 5.80 Impact Factor
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ABSTRACT: Pharmacological treatments for serious mental illness (SMI) can cause weight gain and adverse metabolic effects. Many second generation antipsychotics and mood stabilizers appear to be particularly problematic in this regard. Several studies have investigated interventions for antipsychotic-induced, or less commonly mood stabilizer -induced, weight gain. Both lifestyle and pharmacological interventions have demonstrated effectiveness. We systematically review randomized controlled trials of pharmacological interventions for weight gain related to these medications. We conducted a meta-analysis of clinical trials for the most studied agents to estimate mean weight loss: metformin (2.93 kg, 95% C.I. 0.97-4.89, p=0.003), H(2) antagonists (1.78 kg (95% C.I. -0.50-4.06, p=0.13), topiramate (3.95 kg 95% C.I. 1.77-6.12, p=0.0004), and norepinephrine reuptake inhibitors (1.30 kg (95% C.I. -0.06-2.66, p=0.06). Among the studied options for antipsychotic-related weight gain, metformin has the strongest evidence base and may improve vascular risk factors beyond obesity. The use of topiramate is also supported by the literature and may improve psychotic symptoms in those refractory to treatment. A marginal benefit is seen with norepinephrine reuptake inhibitors, and any vascular benefits from such weight loss may be counteracted by increases in blood pressure or heart rate. Pharmacological therapies may offer benefits as a means of supplementing the effects of lifestyle changes for weight loss. However, the existing evidence provides little evidence of specificity for pharmacological therapies to antipsychotic-induced weight gain and has not studied any connection between benefits and reduced incidence of diabetes mellitus or any vascular outcomes.
Current Psychiatry Reviews 02/2012; 8(1):25-36.
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ABSTRACT: To identify the factors associated with newly prescribed, first-line, second-generation antipsychotics (SgAs) associated with weight gain-olanzapine, risperidone, and quetiapine.
Retrospective medical record review.
Outpatient and inpatient psychiatry services at a tertiary care, academic medical center.
Three hundred forty consecutive adults who had major depressive disorder with psychotic features, bipolar I, bipolar II, bipolar not otherwise specified, or schizoaffective disorder over two time periods (August 30-October 30, 2009, and April 1-May 31, 2010).
Clinical and sociodemographic variables associated with newly prescribed olanzapine, risperidone, and quetiapine were identified by using univariate and multivariate logistic regression. Several clinical factors were individually associated with initiation of these SgAs: mania (odds ratio [OR] 3.6, 95% confidence interval [CI] 1.2-10.8, p=0.02), psychosis (OR 3.3, 95% CI 1.5-6.9, p=0.002), and inpatient treatment (OR 3.8, 95% CI 1.8-7.9, p=0.0005). Prevalent use of lithium (OR 0.3, 95% CI 0.1-0.9, p=0.03) and being married (OR 0.3, 95% CI 0.1-0.8, p=0.02) were inversely associated with new use of an SgA. Mania, psychosis, married status, and lithium use remained independently associated on multivariate analysis. Factors related to metabolic or vascular risk were not associated with SgA initiation.
Psychiatric clinicians were influenced heavily by clinical features related to mental status and acuity when determining whether to prescribe SgAs. However, factors related to vascular risk were not associated. Future observational studies should consider current clinical status as an important factor in determining propensity to receive antipsychotics or other short-term treatments for bipolar and related disorders.
Pharmacotherapy 08/2011; 31(8):806-12. · 2.90 Impact Factor
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ABSTRACT: Little is known about risperidone metabolism in a clinical sample, where polypharmacy is common. Such knowledge is important since several of its side effects are dose dependent.
Medically healthy patients aged 7 to 17 years old treated with risperidone for at least 6 months were enrolled. Trough serum risperidone and 9-hydroxyrisperidone concentrations were measured.
One hundred seven participants (92% males) were recruited, representing a heterogenous clinical group with attention-deficit/hyperactivity disorder, disruptive behavior disorders, pervasive developmental disorders, anxiety disorders, mood disorders, tic disorders, or psychotic disorders. Risperidone had been used at a mean dose of 0.03 mg/kg, for a mean 2.5 years, predominantly to treat irritability and aggression. Cytochrome CYP2D6 inhibitors were divided into prominent (fluoxetine, bupropion, and lamotrigine), intermediate (sertraline), and weak inhibition groups (citalopram or escitalopram). The concentrations of risperidone and its metabolite were strongly associated with the dose of risperidone and time since the last dose and, to a lesser extent, with male sex. In addition, risperidone concentration increased with pubertal stage (p < 0.05), while body mass index z-score (p = 0.001) predicted a higher 9-hydroxyrisperidone concentration. The use of CYP2D6 inhibitors was much more strongly associated with risperidone concentration (p < 0.0001) than with its metabolite's (p = 0.06).
In chronically treated youths, the metabolism of risperidone depends on the stage of sexual development, whereas that of 9-hydroxyrisperidone varies with body fat. Moreover, CYP2D6 inhibitors more strongly affect risperidone metabolism than that of its metabolite. The clinical implications of these findings, in relation to efficacy and tolerability, deserve further investigation.
Journal of child and adolescent psychopharmacology 04/2011; 21(2):163-9. · 2.59 Impact Factor
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Stanley N Caroff,
Vicki G Davis, Del D Miller,
Sonia M Davis,
Robert A Rosenheck,
Joseph P McEvoy,
E Cabrina Campbell,
Bruce L Saltz,
Silvana Riggio,
Miranda H Chakos,
Marvin S Swartz,
Richard S E Keefe,
T Scott Stroup,
Jeffrey A Lieberman
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ABSTRACT: We compared the response to antipsychotic treatment between patients with and without tardive dyskinesia (TD) and examined the course of TD.
This analysis compared 200 patients with DSM-IV-defined schizophrenia and TD and 997 patients without TD, all of whom were randomly assigned to receive one of 4 second-generation antipsychotics. The primary clinical outcome measure was time to all-cause treatment discontinuation, and the primary measure for evaluating the course of TD was change from baseline in Abnormal Involuntary Movement Scale (AIMS) score. Kaplan-Meier survival analysis and Cox proportional hazards regression models were used to compare treatment discontinuation between groups. Changes in Positive and Negative Syndrome Scale (PANSS) and neurocognitive scores were compared using mixed models and analysis of variance. Treatment differences between drugs in AIMS scores and all-cause discontinuation were examined for those with TD at baseline. Percentages of patients meeting criteria for TD postbaseline or showing changes in AIMS scores were evaluated with χ(2) tests. Data were collected from January 2001 to December 2004.
Time to treatment discontinuation for any cause was not significantly different between the TD and non-TD groups (χ(2)(1) = 0.11, P = .743). Changes in PANSS scores were not significantly different (F(1,974) = 0.82, P = .366), but patients with TD showed less improvement in neurocognitive scores (F(1,359) = 6.53, P = .011). Among patients with TD, there were no significant differences between drugs in the decline in AIMS scores (F(3,151) = 0.32, P = .811); 55% met criteria for TD at 2 consecutive visits postbaseline, 76% met criteria for TD at some or all postbaseline visits, 24% did not meet criteria for TD at any subsequent visit, 32% showed a ≥ 50% decrease in AIMS score, and 7% showed a ≥ 50% increase in AIMS score.
Schizophrenia patients with and without TD were similar in time to discontinuation of treatment for any cause and improvement in psychopathology, but differed in neurocognitive response. There were no significant differences between treatments in the course of TD, with most patients showing either persistence of or fluctuation in observable symptoms.
clinicaltrials.gov Identifier: NCT00014001.
The Journal of Clinical Psychiatry 03/2011; 72(3):295-303. · 5.80 Impact Factor
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ABSTRACT: OBJECTIVE: Positive associations between polymorphisms in the type-three metabotropic glutamate receptor gene (GRM3) and the pathogenesis of schizophrenia as well as response to antipsychotic treatment have been reported. The objective of this study was to determine whether refractory psychiatric symptoms in antipsychotic non-responders are related to polymorphisms in GRM3. METHODS: Ninety-five treatment refractory schizophrenia participants were enrolled. Prior to a medication switch, global psychopathology and negative symptoms were rated. These participants were genotyped for seven markers in GRM3. Genotype associations with symptoms were assessed. RESULTS: Two markers in GRM3 (rs1989796 and rs1476455), were associated with the presence of refractory global symptoms as measured by the Brief Psychiatric Rating Scale (BPRS) Total scores. Participants with an rs1476455_CC genotype had significantly higher BPRS scores than A-carriers (55.1 ± 10.4 vs. 48.3 ± 9.2; F = 7.6, p = 0.0071). Additionally, participants with the rs1989796_CC genotype had significantly higher BPRS scores than T-carriers (50.1 ± 5.7 vs. 55.8 ± 10.5, F = 7.1, p = 0.0091). No evidence for significant associations with negative symptoms was observed. CONCLUSIONS: Polymorphisms in the GRM3 gene may be associated with refractory global psychosis symptoms but not negative symptoms in persons with schizophrenia. Copyright © 2011 John Wiley & Sons, Ltd.
Human Psychopharmacology Clinical and Experimental 02/2011; · 2.48 Impact Factor
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ABSTRACT: The wide interindividual variability in clinical response and tolerability of antipsychotic medications has led investigators to postulate that these variabilities may be under genetic control. Although not always consistent, there are promising indications from emergent pharmacogenetic studies that efficacy of antipsychotic medications for the various symptom domains of psychopathology in schizophrenia may be genetically regulated. This is an encouraging approach. Moreover, there are also suggestive findings that the side-effect profiles of second-generation antipsychotic medications and their propensity to cause weight gain and glucose and lipid abnormalities as well as tardive dyskinesia may be related to pharmacogenetic factors in this patient population. Ultimately, such approaches could drive choices of antipsychotic medication based on the likelihood of clinical response and development of side effects in light of a particular patient's genetic profile. In the future, this targeted approach (personalized medicine) may become informative for clinicians choosing an antipsychotic medication for an individual patient with schizophrenia.
Clinics in laboratory medicine 12/2010; 30(4):975-93. · 1.17 Impact Factor
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Karolina Aberg,
Daniel E Adkins,
József Bukszár,
Bradley T Webb,
Stanley N Caroff, Del D Miller,
Jonathan Sebat,
Scott Stroup,
Ayman H Fanous,
Vladimir I Vladimirov,
Joseph L McClay,
Jeffrey A Lieberman,
Patrick F Sullivan,
Edwin J C G van den Oord
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ABSTRACT: Understanding individual differences in the development of extrapyramidal side effects (EPS) as a response to antipsychotic therapy is essential to individualize treatment.
We performed genomewide association studies to search for genetic susceptibility to EPS. Our sample consisted of 738 schizophrenia patients, genotyped for 492K single nucleotide polymorphisms (SNPs). We studied three quantitative measures of antipsychotic adverse drug reactions-the Simpson-Angus Scale (SAS) for Parkinsonism, the Barnes Akathisia Rating Scale, and the Abnormal Involuntary Movement Scale (AIMS)-as well as a clinical diagnosis of probable tardive dyskinesia.
Two SNPs for SAS, rs17022444 and rs2126709 with p = 1.2 x 10(-10) and p = 3.8 x 10(-7), respectively, and one for AIMS, rs7669317 with p = 7.7 x 10(-8), reached genomewide significance (Q value < .1). rs17022444 and rs7669317 were located in intergenic regions and rs2126709 was located in ZNF202 on 11q24. Fourteen additional signals were potentially interesting (Q value < .5). The ZNF202 is a transcriptional repressor controlling, among other genes, PLP1, which is the major protein in myelin. Mutations in PLP1 cause Pelizaeus-Merzbacher disease, which has Parkinsonism as an occurring symptom. Altered mRNA expression of PLP1 is associated with schizophrenia.
Although our findings require replication and validation, this study demonstrates the potential of genomewide association studies to discover genes and pathways that mediate adverse effects of antipsychotics.
Biological psychiatry 10/2009; 67(3):279-82. · 8.93 Impact Factor
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ABSTRACT: Tardive dyskinesia (TD) is a movement disorder characterized by involuntary oro-facial, limb, and truncal movements. As a genetic basis for inter-individual variation is assumed, there have been a sizeable number of candidate gene studies. All subjects met diagnostic criteria for schizophrenia and were randomized to receive antipsychotic medications as participants in the Clinical Antipsychotic Trials of Intervention Effectiveness project (CATIE). TD was assessed via the Abnormal Involuntary Movement Scale at regular intervals. Probable TD was defined as meeting Schooler-Kane criteria at any scheduled CATIE visit (207/710 subjects, 29.2%). A total of 128 candidate genes were studied in 710 subjects-2,580 SNPs in 118 candidate genes selected from the literature (e.g., dopamine, serotonin, glutamate, and GABA pathways) and composite genotypes for 10 drug-metabolizing enzymes. No single marker or haplotype association reached statistical significance after adjustment for multiple comparisons. Thus, we found no support for either novel or prior associations from the literature.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics 06/2009; 153B(1):336-40. · 3.70 Impact Factor
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Del D Miller,
Stanley N Caroff,
Sonia M Davis,
Robert A Rosenheck,
Joseph P McEvoy,
Bruce L Saltz,
Silvana Riggio,
Miranda H Chakos,
Marvin S Swartz,
Richard S E Keefe,
T Scott Stroup,
Jeffrey A Lieberman
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ABSTRACT: There are claims that second-generation antipsychotics produce fewer extrapyramidal side-effects (EPS) compared with first-generation drugs.
To compare the incidence of treatment-emergent EPS between second-generation antipsychotics and perphenazine in people with schizophrenia.
Incidence analyses integrated data from standardised rating scales and documented use of concomitant medication or treatment discontinuation for EPS events. Mixed model analyses of change in rating scales from baseline were also conducted.
There were no significant differences in incidence or change in rating scales for parkinsonism, dystonia, akathisia or tardive dyskinesia when comparing second-generation antipsychotics with perphenazine or comparing between second-generation antipsychotics. Secondary analyses revealed greater rates of concomitant antiparkinsonism medication among individuals on risperidone and lower rates among individuals on quetiapine, and lower rates of discontinuation because of parkinsonism among people on quetiapine and ziprasidone. There was a trend for a greater likelihood of concomitant medication for akathisia among individuals on risperidone and perphenazine.
The incidence of treatment-emergent EPS and change in EPS ratings indicated that there are no significant differences between second-generation antipsychotics and perphenazine or between second-generation antipsychotics in people with schizophrenia.
The British journal of psychiatry: the journal of mental science 11/2008; 193(4):279-88. · 6.62 Impact Factor
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ABSTRACT: Bipolar disorder is associated with excess cardiovascular mortality. We hypothesized outpatients with bipolar disorder would exhibit excess cardiovascular risk factors, particularly among prevalent users of the second-generation antipsychotics associated with weight gain and valproic acid derivatives.
This chart review of 217 patients with bipolar disorder examined cardiovascular risk factors of the metabolic syndrome. We also evaluated if certain medications were cross-sectionally associated with metabolic syndrome.
Fifty-six patients were not weighed and many did not have available lipid profiles. Over three-quarters of those with available data (n = 161) were overweight or obese (body mass index >or= 25) and nearly half were obese (body mass index >or= 30). A prevalence exceeding general population estimates was also observed for hypertriglyceridemia, elevated blood pressure/hypertension, and elevated fasting glucose/diabetes. Among those with all requisite data (n = 60), over 50% met criteria for National Cholesterol Education Program-defined metabolic syndrome, nearly double the expected prevalence. A trend toward greater prevalence of metabolic syndrome among prevalent users of the second-generation antipsychotics associated with weight gain was observed.
Obesity and the metabolic syndrome were common in patients with bipolar disorder. These patients may be under-evaluated for cardiovascular risk and warrant screening and early intervention.
Annals of Clinical Psychiatry 07/2008; 20(3):131-7. · 1.49 Impact Factor
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Marvin S Swartz,
H Ryan Wagner,
Jeffrey W Swanson,
T Scott Stroup,
Joseph P McEvoy,
Fred Reimherr, Del D Miller,
Mark McGee,
Ahsan Khan,
Jose M Canive,
Sonia M Davis,
John K Hsiao,
Jeffrey A Lieberman
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ABSTRACT: This double-blind study compared a second generation (atypical) antipsychotic drugs compared to a representative older agent for patients with schizophrenia who use or avoid illicit substances.
Schizophrenic subjects were recruited at 57 U.S. sites and randomly assigned to olanzapine, perphenazine, quetiapine, risperidone or ziprasidone for up to 18 months. The primary aim of this analysis was to delineate differences between the overall effectiveness of these five treatments among patients who used or did not use illicit substances.
There were no significant differences between treatment groups in time to all-cause treatment discontinuation among patients who use illicit drugs (median 3.3 to 6.8 months). Among non-users time to treatment discontinuation was significantly longer for patients treated with olanzapine (median 13.0 months) than perphenazine ( 5.9 months), risperidone (5.6 months), or quetiapine (5.0 months); time to discontinuation for ziprasidone (4.3 months) was even shorter, although the latter difference was not significant. The difference between risperidone and quetiapine, although small, was significant. All remaining differences were non-significant. Similar results were found for discontinuation due to inefficacy. There were no differences between illicit users and non-users in symptom reduction and global improvement, after adjustment for differential duration of treatment. Differences in discontinuation results were attenuated by non-compliance, but the trends persisted after controlling for treatment compliance.
Among patients with chronic schizophrenia who avoid use of illicit drugs, olanzapine was more effective than other antipsychotics as reflected by longer time to all-cause discontinuation, but illicit substance abuse attenuated this advantage, reinforcing the need for concurrent substance abuse treatment.
Schizophrenia Research 04/2008; 100(1-3):39-52. · 4.75 Impact Factor
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ABSTRACT: Response to antipsychotics is highly variable, which may be due in part to differences in drug exposure. The goal of this study was to evaluate the magnitude and variability of concentration exposure of olanzapine. Patients with Alzheimer's disease (n = 117) and schizophrenia (n = 406) were treated with olanzapine as part of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE). Combined, these patients (n = 523) provided 1527 plasma samples for determination of olanzapine concentrations. Nonlinear mixed-effects modeling was used to determine the population pharmacokinetics of olanzapine, and patient-specific covariates were evaluated as potential contributors to variability in drug exposure. The population mean olanzapine clearance and volume of distribution were 16.1 L/h and 2150 L, respectively. Elimination of olanzapine varied nearly 10-fold (range, 6.66-67.96 L/h). Smoking status, sex, and race accounted for 26%, 12%, and 7% of the variability, respectively (P < .0001). Smokers cleared olanzapine 55% faster than non/past smokers (P < .0001). Men cleared olanzapine 38% faster than women (P < .0001). Patients who identified themselves as black or African American cleared olanzapine 26% faster than other races (P < .0001). Differences in olanzapine exposure due to sex, race, and smoking may account for some of the variability in response to olanzapine.
The Journal of Clinical Pharmacology 02/2008; 48(2):157-65. · 2.91 Impact Factor
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ABSTRACT: The metabolic syndrome and insulin resistance represent growing concerns related to atypical antipsychotic (AAP) use as their incidence in the schizophrenia population is two-to-four-fold higher than the general population. Reduced methylenetetrahydrofolate reductase (MTHFR) activity, resulting in aberrant folate metabolism and hyperhomocysteinemia, has been linked to cardiovascular disease and is unstudied in relation to AAP associated metabolic complications.
To examine the relationship between MTHFR, metabolic syndrome, and insulin resistance in schizophrenia subjects receiving AAPs for >or=12 months.
Fifty-eight subjects were included in this cross-sectional analysis and screened for the metabolic syndrome, insulin resistance and MTHFR 677C/T and 1298A/C genotype.
Overall, 23 subjects (40%) met metabolic syndrome criteria. There were no differences in age, gender, race, or AAP exposure between genotype groups. For the 677 T allele carriers, 53% met metabolic syndrome criteria, compared to 23% in the CC genotype group, giving an OR=3.7, (95% CI=1.24-12.66, p=0.02). Thus, for T allele subjects, the risk was almost four times greater, despite similar antipsychotic exposure. Both waist circumference and MTHFR genotype significantly predicted insulin resistance (F=8.35, df=5, 51, p<0.0001), with these two terms interacting (F=8.6, df=2, p=0.0006) suggesting that TT subjects are at greater risk for insulin resistance with increasing central adiposity, which is independent of age, gender, BMI, or metabolic syndrome diagnosis.
Results should be taken cautiously due to the small sample size, but suggest the MTHFR 677C/T variant may predispose patients to AAP metabolic complications.
Schizophrenia Research 01/2008; 98(1-3):47-54. · 4.75 Impact Factor
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ABSTRACT: To comparatively assess the incidence of tardive dyskinesia in patients with schizophrenia receiving either aripiprazole or haloperidol.
Data from 2 controlled, long-term trials of subjects meeting DSM-IV criteria for schizophrenia treated with aripiprazole (N = 861, 20-30 mg/day) or haloperidol (N = 433, 5-10 mg/day) were analyzed. The primary outcome measure was the rate of new-onset tardive dyskinesia. The analysis was limited to patients without baseline tardive dyskinesia. There were no significant differences between treatment groups in demographic or disease characteristics. The Abnormal Involuntary Movement Scale (AIMS) and Research Diagnostic Criteria for tardive dyskinesia were used to define the comparative incidence rates of long-term treatment-emergent tardive dyskinesia.
A significantly lower percentage of aripiprazole-treated patients developed new-onset tardive dyskinesia compared with haloperidol-treated patients (p < .0001). The annualized rate of treatment-emergent tardive dyskinesia was significantly lower in aripiprazole-treated versus haloperidol-treated patients. In patients without a baseline diagnosis of tardive dyskinesia, aripiprazole significantly improved AIMS scores compared with haloperidol (p <or= .0001).
These findings support the potential for a significantly lower risk of tardive dyskinesia with aripiprazole than with haloperidol among patients requiring maintenance antipsychotic treatment.
The Journal of Clinical Psychiatry 12/2007; 68(12):1901-6. · 5.80 Impact Factor
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Troy A Moore,
Robert W Buchanan,
Peter F Buckley,
John A Chiles,
Robert R Conley,
M Lynn Crismon,
Susan M Essock,
Molly Finnerty,
Stephen R Marder, Del D Miller,
Joseph P McEvoy,
Delbert G Robinson,
Nina R Schooler,
Steven P Shon,
T Scott Stroup,
Alexander L Miller
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ABSTRACT: A panel of academic psychiatrists and pharmacists, clinicians from the Texas public mental health system, advocates, and consumers met in June 2006 in Dallas, Tex., to review recent evidence in the pharmacologic treatment of schizophrenia. The goal of the consensus conference was to update and revise the Texas Medication Algorithm Project (TMAP) algorithm for schizophrenia used in the Texas Implementation of Medication Algorithms, a statewide quality assurance program for treatment of major psychiatric illness.
Four questions were identified via premeeting teleconferences. (1) Should antipsychotic treatment of first-episode schizophrenia be different from that of multiepisode schizophrenia? (2) In which algorithm stages should first-generation antipsychotics (FGAs) be an option? (3) How many antipsychotic trials should precede a clozapine trial? (4) What is the status of augmentation strategies for clozapine? Subgroups reviewed the evidence in each area and presented their findings at the conference.
The algorithm was updated to incorporate the following recommendations. (1) Persons with first-episode schizophrenia typically require lower antipsychotic doses and are more sensitive to side effects such as weight gain and extrapyramidal symptoms (group consensus). Second-generation antipsychotics (SGAs) are preferred for treatment of first-episode schizophrenia (majority opinion). (2) FGAs should be included in algorithm stages after first episode that include SGAs other than clozapine as options (group consensus). (3) The recommended number of trials of other antipsychotics that should precede a clozapine trial is 2, but earlier use of clozapine should be considered in the presence of persistent problems such as suicidality, comorbid violence, and substance abuse (group consensus). (4) Augmentation is reasonable for persons with inadequate response to clozapine, but published results on augmenting agents have not identified replicable positive results (group consensus).
These recommendations are meant to provide a framework for clinical decision making, not to replace clinical judgment. As with any algorithm, treatment practices will evolve beyond the recommendations of this consensus conference as new evidence and additional medications become available.
The Journal of Clinical Psychiatry 12/2007; 68(11):1751-62. · 5.80 Impact Factor
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ABSTRACT: Emergent pharmacogenetic studies indicate that the efficacy of antipsychotic medications in schizophrenia may be predicted through genetic analysis. There also is evidence that the side-effect profiles of second-generation antipsychotic medications and their propensity to cause weight gain, glucose and lipid abnormalities, and tardive dyskinesia may be predicted by pharmacogenetic analysis in this patient population. In the future, this targeted approach with the choice of antipsychotic medication based on the likelihood of clinical response and development of side effects in light of a particular patient's genetic status may gain hold as new treatments are developed with even fewer side effects.
The Psychiatric clinics of North America 10/2007; 30(3):417-35. · 1.87 Impact Factor
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ABSTRACT: The objective of the current investigation was to determine the relationship between polymorphisms of the leptin system (leptin gene and leptin receptor) and olanzapine-induced weight gain in persons with schizophrenia.
Pharmacogenetic association reanalysis of a longitudinal, open label, six week, fixed dose trial of olanzapine response and adverse effects.
Thirty-seven males and females with clinically symptomatic schizophrenia (age, 23-52) meeting DSM-IV criteria.
Baseline and endpoint weight, BMI, olanzapine dose, plasma levels, and psychopathology measures were completed in a prior study. These subjects were subsequently genotyped for the -1548 G/A polymorphism of the leptin gene and the Q223R polymorphism of the leptin receptor. The relationship between alleles at each locus, olanzapine plasma levels, and percent change in body mass index (BMI) from baseline were conducted.
Genotypes and alleles for each locus were not individually associated with olanzapine-induced weight gain in this study population. Changes in BMI from baseline increased significantly in persons with olanzapine plamsa levels >20.6 ng/mL for subjects carrying at least one G allele at both candidate loci compared to those who did not have a G allele at each (P = 0.049).
This study suggests that genetic variability in the leptin gene and leptin receptor may predispose some individuals to excessive weight gain from increased exposure to olanzapine.
Psychopharmacology bulletin 01/2007; 40(1):57-62. · 1.35 Impact Factor
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ABSTRACT: P-glycoprotein (PGP) is a polymorphic efflux transporter located on the blood brain barrier that potentially affects the penetration of atypical antipsychotics into the central nervous system. Increased antipsychotic penetration to the primary site of activity may result in greater symptom improvement or the occurrence of side effects. This investigation examined the relationship between three common PGP polymorphisms (C1236T, G2677TA, and C3435T) and response to 6 weeks of open-label olanzapine treatment in patients with schizophrenia. Individuals with a PGP T allele at any of these polymorphisms would be expected to have greater antipsychotic penetration through the blood brain barrier, due to lower PGP activity. Forty-one patients were included in this reanalysis. For subjects in the 3435T allele carrier group, the plasma olanzapine level alone was positively associated with percent change in Brief Psychiatric Rating Scale score (p = 0.02). This relationship was not seen for the 3435CC group (p = 0.583). A similar trend was observed for negative symptom reduction, olanzapine plasma concentration, and the 3435T allele (p = 0.06), but this relationship did not meet statistical significance. There was no relationship between the PGP genotypes and changes in weight over the course of this 6 week study. The analysis using C1236T or G2677AT genotypes gave similar results, due to linkage of these polymorphisms.PGP polymorphisms may affect the penetration of olanzapine into the central nervous system as seen by a relationship between the 3435T allele, olanzapine plasma levels, and reduction in the positive symptoms of schizophrenia. This may stem from greater olanzapine central nervous system latency due to the presence of the 3435T allele and reduced PGP activity. The PGP C3435T genotype may help to determine positive symptom reduction from olanzapine clinically, but these findings should be replicated in a larger sample of subjects.
Therapeutic Drug Monitoring 11/2006; 28(5):668-72. · 2.49 Impact Factor
