Pharmacotherapy for treatment-resistant schizophrenia

Abstract

Schizophrenia is a disabling mental illness with a lifetime prevalence of 0.7% worldwide and significant, often devastating, consequences on social and occupational functioning. A range of antipsychotic medications are available; however, suboptimal therapeutic response in terms of psychotic symptoms is common and affects up to one-third of people with schizophrenia. Negative symptoms are generally less amenable to treatment. Because of the consequences of inadequate symptom control, effective treatment strategies are required for people with treatment-resistant schizophrenia. Clozapine has been shown to be more effective than other antipsychotics in treatment-resistant populations in several studies; however, the occurrence of adverse effects, some of which are potentially life-threatening, are important limitations. In addition to those who are intolerant to clozapine, only 30% to 50% experience clinically significant symptom improvement. This review describes the recent evidence for treatment strategies for people not responding to nonclozapine antipsychotic agents and people not responding or only partially responding to clozapine.

Glutamatergic Neurometabolites in Clozapine-Responsive and -Resistant Schizophrenia

“…While current medications for schizophrenia work primarily by blocking D 2 -type dopamine receptors ( Kapur et al, 2000 ; McIlwain et al, 2011 ), recent theories suggest that abnormalities in glutamatergic neurotransmission may underlie the deteriorating course of schizophrenia, ultimately leading to dopaminergic dysregulation ( Olney and Farber, 1995 ; Sharp et al, 2001 ). The N -methyl d -aspartate (NMDA) receptor model suggests that hypofunctioning of these receptors in gamma-aminobutyric acid (GABA) interneurons causes a paradoxical, compensatory increase in presynaptic glutamate (Glu) release while GABA synthesis and release is downregulated ( Lisman et al, 2008 ).…”

<p>The Effect of Liver and Kidney Disease on the Pharmacokinetics of Clozapine and Sildenafil: A Physiologically Based Pharmacokinetic Modeling</p>

“…2 Clozapine is a tricyclic dibenzodiazepine, which is considered to be remarkably efficient in the treatment of schizophrenia, specifically in treatment-resistant schizophrenia. 3 Clozapine is metabolized by the cytochrome P450 (CYP) system of enzymes in the liver, yielding a pharmacologically active metabolite, norclozapine. The most influential CYP isoformin on clozapine metabolism is CYP1A2, which has a major impact on the determination of the dose of the drug.…”

“…9 Moreover, clozapine is prescribed to lessen the risk of recurrent suicidal behavior in schizophrenic patients. 3 The occurrence of extrapyramidal adverse events is considered rare with clozapine therapy. However, clozapine is sometimes limited to cases of treatment-resistant schizophrenia, as a result of its significant risks.…”

Acute onset clozapine-induced hyperglycaemia: A case report

“…In clinical practice, the use of clozapine is usually reserved for those patients who do not respond adequately to previous trials of other antipsychotic medications 2. The therapeutic efficacy of clozapine is reported to be higher than that of other antipsychotics and the side effects reported are also higher 3. Various studies showed that the prevalence of metabolic syndrome among subjects taking clozapine was much higher than that of the subjects taking other antipsychotics 4.…”