olanzapine and Depressive-Disorder--Treatment-Resistant

Objective Augmentation of antidepressants with atypical antipsychotics is used in depressive patients with non-response to antidepressants. We investigated the utility of this strategy.Methods Systematic computer-based search in the online library Pubmed for randomized placebo-controlled double-blind trials (RCT) from the years 1990 to 2011.Results We found 14 RCT about augmentation of antidepressants with atypical antipsychotics in depressive patients with non-response to antidepressants. Trials examined olanzapine, risperidone, quetiapine and aripiprazole.Conclusions Augmentation of antidepressants with atypical antipsychotics is an alternative to the augmentation with lithium in unipolar depressive patients with non-response to antidepressants. But treatment with atypical antipsychotics as opposed to placebo increases the risk of non-compliance due to side-effects of medication. Augmentation of antidepressants with atypical antipsychotics in unipolar depression is an off-label therapy in Germany except for the augmentation with extended-release quetiapine. Knowledge about treatment strategies regarding augmentation of antidepressants with atypical antipsychotics can increase the chance of a successful treatment, but interactions and side-effects should be considered.

Topics: Antidepressive Agents; Antimanic Agents; Antipsychotic Agents; Aripiprazole; Benzodiazepines; Depressive Disorder, Treatment-Resistant; Dibenzothiazepines; Double-Blind Method; Drug Therapy, Combination; Humans; Lithium Carbonate; Olanzapine; Patient Compliance; Piperazines; Quetiapine Fumarate; Quinolones; Randomized Controlled Trials as Topic; Risperidone

To determine whether single-nucleotide polymorphisms (SNPs) in candidate genes are associated with response to olanzapine-fluoxetine combination.. A post hoc analysis of a priori-selected SNPs used data from a clinical trial (dates: April 2002-July 2005) of olanzapine-fluoxetine combination, fluoxetine, and olanzapine in patients with major depressive disorder (DSM-IV criteria) and with nonresponse to prestudy antidepressant treatment and nonresponse to fluoxetine treatment during the study. Patients received open-label treatment with fluoxetine for 8 weeks (2 weeks, 25 mg/d; then 6 weeks, 50 mg/d), at the end of which nonresponders (< 25% decline in the 17-item Hamilton Depression Rating Scale score) were randomized to receive double-blind, monotherapy treatment with olanzapine-fluoxetine combination (6/50-18/50 mg/d, n = 71), fluoxetine (50 mg/d, n = 78), or olanzapine (6-18 mg/d, n = 56) for 8 weeks. Statistical significance was assessed at P < .05. The primary efficacy measure for within-study treatment was improvement on the Montgomery-Asberg Depression Rating Scale (MADRS).. Rs36024, an intronic SNP in the norepinephrine transporter (SLC6A2), as well as 3 SNPs in melanocortin 3 receptor (MC3R) and 2 SNPs in tryptophan hydroxylase 2 (TPH2), were associated with MADRS-defined response to treatment with olanzapine-fluoxetine combination (adjusted Li-Nyholt P < .05). Except for 1 SNP in TPH2, identified SNPs were not significantly associated with response to continued-fluoxetine or olanzapine treatments.. Our findings further support the hypothesis that the synergistic effect of olanzapine and fluoxetine on prefrontal cortical levels of norepinephrine and dopamine might be an underlying mechanism for the efficacy of olanzapine-fluoxetine combination in the treatment of treatment-resistant depression and, if replicated, may form a basis on which response to olanzapine-fluoxetine combination versus continued fluoxetine can be predicted based on variants in SLC6A2.. Parent study registered at ClinicalTrials.gov identifier: NCT00035321.

Topics: Antidepressive Agents, Second-Generation; Benzodiazepines; Depressive Disorder, Treatment-Resistant; Double-Blind Method; Drug Combinations; Fluoxetine; Genetic Association Studies; Genotype; Humans; Linkage Disequilibrium; Norepinephrine Plasma Membrane Transport Proteins; Olanzapine; Polymorphism, Single Nucleotide; Psychiatric Status Rating Scales; Receptor, Melanocortin, Type 3; Selective Serotonin Reuptake Inhibitors; Tryptophan Hydroxylase

Pharmacogenomic analyses of weight gain during treatment with second-generation antipsychotics have resulted in a number of associations with variants in ankyrin repeat and kinase domain containing 1 (ANKK1)/dopamine D2 receptor (DRD2) and serotonin 2C receptor (HTR2C) genes. These studies primarily assessed subjects with schizophrenia who had prior antipsychotic exposure that may have influenced the amount of weight gained from subsequent therapies. We assessed the relationships between single-nucleotide polymorphisms (SNPs) in these genes with weight gain during treatment with olanzapine in a predominantly antipsychotic-naive population.. The association between 5 ANKK1, 54 DRD2, and 11 HTR2C SNPs and weight change during 8 weeks of olanzapine treatment was assessed in 4 pooled studies of 205 white patients with diagnoses other than schizophrenia who were generally likely to have had limited previous antipsychotic exposure.. The A allele of DRD2 rs2440390(A/G) was associated with greater weight gain in the entire study sample (P = .0473). Three HTR2C SNPs in strong linkage disequilibrium, rs6318, rs2497538, and rs1414334, were associated with greater weight gain in women but not in men (P = .0032, .0012, and .0031, respectively). A significant association with weight gain for 2 HTR2C SNPs previously reported associated with weight gain, -759C/T (rs3813929) and -697G/C (rs518147), was not found.. Associations between weight gain and HTR2C and DRD2 variants in whites newly exposed to olanzapine may present opportunities for the individualization of medication selection and development based on differences in adverse events observed across genotype groups.

Topics: Adult; Alleles; Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Borderline Personality Disorder; Depressive Disorder, Treatment-Resistant; Female; Genetic Association Studies; Humans; Linkage Disequilibrium; Male; Mental Disorders; Middle Aged; Olanzapine; Pharmacogenetics; Polymorphism, Single Nucleotide; Risperidone; Schizophrenia; Weight Gain

Topics: Adult; Akathisia, Drug-Induced; Antidepressive Agents; Depressive Disorder, Treatment-Resistant; Humans; Ketamine; Male; Olanzapine; Substance Withdrawal Syndrome

Recent clinical studies report antipsychotics as a better option to augment the action of antidepressants in treatment resistant cases. However, the proper mechanisms underlying the antidepressant effect of antipsychotics is still not clear. Indolamine 2, 3 dioxygenase (IDO) pathway is considered to be an important pathway in pro-inflammatory cytokine associated stress-induced depression. The present study investigated the antidepressant effect of venlafaxine, olanzapine and their combinations in chronic forced-swim stress-induced depression in mice. In addition, the role of pro-inflammatory cytokines and IDO-mediated pathway was investigated. Swiss albino mice were subjected to chronic forced-swim stress and evaluation for antidepressant-like activity was performed on 7th, 14th and 21st day following which serum levels of pro-inflammatory cytokines (IL-1β and IL-6 levels) and the levels of hippocampal kynurenine (KYN), tryptophan (TRP) and serotonin (5HT) were estimated. The combination exhibited augmentation of antidepressant-like activity of venlafaxine by olanzapine in chronic forced-swim stress model. Further, it reversed the enhanced serum IL-1β and IL-6 and reverted the increased activity of IDO as measured by ratio of hippocampal KYN/TRP and 5HT/TRP in stressed mice. Augmentation of antidepressant effect of venlafaxine by olanzapine is thus mediated by normalising the shift from KYN to TRP pathway in chronic forced swim induced stressed mice.

Topics: Animals; Antidepressive Agents; Antipsychotic Agents; Benzodiazepines; Depression; Depressive Disorder, Treatment-Resistant; Female; Hippocampus; Indoleamine-Pyrrole 2,3,-Dioxygenase; Inflammation; Interleukin-1beta; Interleukin-6; Kynurenine; Male; Mice; Olanzapine; Serotonin; Stress, Psychological; Swimming; Tryptophan; Venlafaxine Hydrochloride

Olanzapine augmentation of fluoxetine, a selective serotonin reuptake inhibitor, is an effective augmentation therapy for treatment-resistant depression (TRD). However, studies of olanzapine augmentation of other antidepressants are few. We investigated the efficacy and safety of olanzapine augmentation of milnacipran, a serotonin-norepinephrine reuptake inhibitor, for TRD.. This study covered patients with stage 2 TRD, defined by Thase and Rush. Olanzapine was added to milnacipran, and its dosage was adjusted according to each patient. Previous treatments were continued, but no new treatments were allowed. Response was measured using Hamilton Depression Rating Scale (HAMD) and Clinical Global Impression at weeks 0, 1, 2, 3, 4, and 8.. Eleven patients aged 53.2 ± 24.0 years received olanzapine at 5.0 ± 1.9 mg/day with milnacipran. HAMD and Clinical Global Impression scores improved significantly from baseline to endpoint. This improvement occurred in week 1. At endpoint, seven of 11 (64%) were responders on HAMD (≥ 50% reduction). Four patients (36%) discontinued the trial because of no efficacy. No severe adverse effect occurred.. Olanzapine augmentation of milnacipran for stage 2 TRD might be effective and well tolerated. However, our study is open label and uncontrolled. Therefore, a double-blind controlled trial is necessary to confirm our results.

Topics: Adolescent; Adult; Aged; Benzodiazepines; Cyclopropanes; Depressive Disorder, Major; Depressive Disorder, Treatment-Resistant; Drug Synergism; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Milnacipran; Olanzapine; Young Adult

Olanzapine is an antipsychotic used in the treatment of schizophrenia, bipolar disorder, and treatment-resistant depression. Glucuronidation by the UDP-glucuronosyltransferase (UGT) family of enzymes is the major mode of olanzapine metabolism, and polymorphisms in these enzymes could contribute to interindividual variability in olanzapine metabolism and therapeutic response.. Cell lines overexpressing individual UGT enzymes were used to determine which UGTs have enzymatic activity against olanzapine, characterize the kinetics of this reaction, and examine the effects of UGT variants on olanzapine metabolism. A bank of 105 human liver microsomes (HLM) were used to perform a phenotype-genotype study comparing glucuronidation activity against UGT genotype.. Cell lines overexpressing the individual UGTs 1A4 and 2B10 exhibited glucuronidation activity against olanzapine. The UGT1A4 variant exhibited a 3.7-fold (P<0.0001) higher Vmax/KM for the formation of the olanzapine-10-N-glucuronide isomer 1, and a 4.3-fold (P<0.0001) higher Vmax/KM for the formation of the olanzapine-10-N-glucuronide isomer 2 than wild-type UGT1A4. The UGT2B10 variant exhibited no glucuronidation activity against olanzapine. In a screening of 105 HLM specimens, there was a 2.1-fold (P=0.04) and 1.6-fold (P=0.0017) increase in the rate of olanzapine-10-N-glucuronide isomer 1 and olanzapine-4'-N-glucuronide formation, and a 2-fold (P=0.02) increase in the overall olanzapine glucuronidation formation, in HLM with the UGT1A4 (*3/*3)/UGT2B10 (*1/*1) genotype compared with HLM with the UGT1A4 (*1/*1)/UGT2B10 (*1/*1) genotype. There was a 1.9-fold (P<0.003) decrease in the formation of both isomers of the olanzapine-10-N-glucuronide, a 2.7-fold (P<0.0001) decrease in olanzapine-4'-N-glucuronide formation, and a 2.1-fold (P=0.0002) decrease in the overall olanzapine glucuronide formation in HLM with at least one UGT2B10*2 allele. In regression analysis, the UGT1A4*3 (P<0.02) and UGT2B10*2 (P<0.002) alleles were significant predictors of the formation of all olanzapine glucuronide isomers.. The UGTs 1A4 and 2B10 glucuronidate olanzapine and functional variants of these UGTs significantly alter olanzapine glucuronidation in vitro. These data suggest that the UGT1A4*3 and UGT2B10*2 alleles contribute significantly to interindividual variability in olanzapine metabolism.

Topics: Antipsychotic Agents; Benzodiazepines; Biomarkers, Pharmacological; Bipolar Disorder; Cell Line; Depressive Disorder, Treatment-Resistant; Genetic Association Studies; Genetic Variation; Genotype; Glucuronosyltransferase; Humans; Microsomes, Liver; Olanzapine; Polymorphism, Single Nucleotide; Regression Analysis; Schizophrenia