Current perspectives in the treatment of resistant schizophrenia

Solanki, RK; Singh, P. P.; Munshi, Deepti

doi:10.4103/0019-5545.58289

Cited by 34 publications

(19 citation statements)

References 87 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The rate of treatment-resistant schizophrenia (TRS) is estimated to be between 30 and 60%, depending on which criteria are used (Solanki et al, 2009). If first-line treatments prove ineffective, there are still many options available, not least the gold standard, clozapine.…”

Section: Introductionmentioning

confidence: 99%

Use of very-high-dose olanzapine in treatment-resistant schizophrenia

Batail

Langrée

Robert

et al. 2014

Schizophrenia Research

View full text Add to dashboard Cite

Schizophrenia is a chronic illness with a progressive course that can be marked by resistance to antipsychotic treatment. This can make therapeutic support challenging for the practitioner, with results that are partial and unsatisfactory. In the literature, treatment with high-dose olanzapine (>20mg/day) appears to be a good alternative to clozapine, the gold standard for treatment-resistant schizophrenia. In the present observational prospective study, we studied the clinical and biological profiles of patients treated with olanzapine doses up to 100mg/day. In total, 50 patients were clinically and biologically assessed. We found a linear relationship between oral dose and serum concentration (Pearson's r=0.83, p<0.001) with effects of tobacco (p<0.05) and of coffee and tea consumption (p<0.01). Tolerance seemed to be good regardless of dose. No link was found between concentration and efficiency. Despite a nonexhaustive assessment of pharmacokinetic parameters, not least pharmacogenetic data (e.g., genotyping of cytochrome P450-1A2 or glycoprotein P Abcb1a), pharmacokinetic aspects alone cannot account for why the disease may sometimes be resistant to 20mg of olanzapine but respond to higher doses. A nuclear imaging study exploring brain occupancy by high-dose olanzapine, coupled with the abovementioned pharmacokinetic assessment, may prove a relevant experimental paradigm for studying the pathophysiological mechanisms of resistant schizophrenia.

show abstract

Section: Introductionmentioning

confidence: 99%

Use of very-high-dose olanzapine in treatment-resistant schizophrenia

Batail

Langrée

Robert

et al. 2014

Schizophrenia Research

View full text Add to dashboard Cite

show abstract

“…This enzyme synthesizes cAMP from ATP; thus, current antipsychotics with D 2 antagonism or partial agonism are thought to produce antipsychotic effects via activation of the indirect pathway by promoting cAMP production. However, approximately 30% of patients with schizophrenia receive little or no benefit from current antipsychotics, and the use of typical antipsychotics can be associated with mechanism‐related side effects such as extrapyramidal symptoms (EPS) and hyperprolactinemia . Even atypical antipsychotics with a lower incidence of EPS than typical antipsychotics are still associated with hyperprolactinemia and serious metabolic side effects .…”

Section: Introductionmentioning

confidence: 99%

Combined treatment with a selective PDE10A inhibitor TAK‐063 and either haloperidol or olanzapine at subeffective doses produces potent antipsychotic‐like effects without affecting plasma prolactin levels and cataleptic responses in rodents

Suzuki

Harada

Suzuki

et al. 2017

Pharmacology Res & Perspec

View full text Add to dashboard Cite

Activation of indirect pathway medium spiny neurons (MSNs) via promotion of cAMP production is the principal mechanism of action of current antipsychotics with dopamine D2 receptor antagonism. TAK‐063 [1‐[2‐fluoro‐4‐(1H‐pyrazol‐1‐yl)phenyl]‐5‐methoxy‐3‐(1‐phenyl‐1H‐pyrazol‐5‐yl)pyridazin‐4(1H)‐one] is a novel phosphodiesterase 10A inhibitor that activates both direct and indirect pathway MSNs through increasing both cAMP and cGMP levels by inhibition of their degradation. The activation of indirect pathway MSNs through the distinct mechanism of action of these drugs raises the possibility of augmented pharmacological effects by combination therapy. In this study, we evaluated the potential of combination therapy with TAK‐063 and current antipsychotics, such as haloperidol or olanzapine after oral administration. Combined treatment with TAK‐063 and either haloperidol or olanzapine produced a significant increase in phosphorylation of glutamate receptor subunit 1 in the rat striatum. An electrophysiological study using rat corticostriatal slices showed that TAK‐063 enhanced N‐methyl‐D‐aspartic acid receptor‐mediated synaptic responses in both direct and indirect pathway MSNs to a similar extent. Further evaluation using pathway‐specific markers revealed that coadministration of TAK‐063 with haloperidol or olanzapine additively activated the indirect pathway, but not the direct pathway. Combined treatment with TAK‐063 and either haloperidol or olanzapine at subeffective doses produced significant effects on methamphetamine‐ or MK‐801‐induced hyperactivity in rats and MK‐801‐induced deficits in prepulse inhibition in mice. TAK‐063 at 0.1 mg/kg did not affect plasma prolactin levels and cataleptic response from antipsychotics in rats. Thus, TAK‐063 may produce augmented antipsychotic‐like activities in combination with antipsychotics without effects on plasma prolactin levels and cataleptic responses in rodents.

show abstract

“…Approximately 30% of patients fail two or more trials with AP drugs, and are subsequently diagnosed with TRS. For these individuals, CLZ is the one drug that has been approved for treatment of this particular subpopulation of patients [8,9,10]. Response to CLZ is complex and thought to depend, at least in part, on genetic factors, as indicated by twin and family studies [11,12,13,14].…”

Section: Introductionmentioning

confidence: 99%

Pharmacogenetic Analysis of Functional Glutamate System Gene Variants and Clinical Response to Clozapine

Taylor¹,

Tiwari²,

Lieberman

et al. 2016

Complex Psychiatry

View full text Add to dashboard Cite

Altered glutamate neurotransmission is implicated in the etiology of schizophrenia (SCZ) and the pharmacogenetics of response to clozapine (CLZ), which is the drug of choice for treatment-resistant SCZ. Response to antipsychotic therapy is highly variable, although twin studies suggest a genetic component. We investigated the association of 10 glutamate system gene variants with CLZ response using standard genotyping procedures. GRM2 (rs4067 and rs2518461), SLC1A2 (rs4354668, rs4534557, and rs2901534), SLC6A9 (rs12037805, rs1978195, and rs16831558), GRIA1 (rs2195450), and GAD1 (rs3749034) were typed in 163 European SCZ/schizoaffective disorder patients deemed resistant or intolerant to previous pharmacotherapy. Response was assessed following 6 months of CLZ monotherapy using change in Brief Psychiatric Rating Scale (BPRS) scores. Categorical and continuous response variables were analyzed using χ² tests and analysis of covariance, respectively. We report no significant associations following correction for multiple testing. Prior to correction, nominally significant associations were observed for SLC6A9, SLC1A2, GRM2, and GRIA1. Most notably, CC homozygotes of rs16831558 located in the glycine transporter 1 gene (SLC6A9) exhibited an allele dose-dependent improvement in positive symptoms compared to T allele carriers (p_uncorrected = 0.008, p_corrected = 0.08). To clarify the role of SLC6A9 in clinical response to antipsychotic medication, and CLZ in particular, this finding warrants further investigation in larger well-characterized samples.

show abstract

Current perspectives in the treatment of resistant schizophrenia

Cited by 34 publications

References 87 publications

Use of very-high-dose olanzapine in treatment-resistant schizophrenia

Use of very-high-dose olanzapine in treatment-resistant schizophrenia

Combined treatment with a selective PDE10A inhibitor TAK‐063 and either haloperidol or olanzapine at subeffective doses produces potent antipsychotic‐like effects without affecting plasma prolactin levels and cataleptic responses in rodents

Pharmacogenetic Analysis of Functional Glutamate System Gene Variants and Clinical Response to Clozapine

Contact Info

Product

Resources

About