Body mass index, waist circumference, insulin, and leptin plasma levels differentiate between clozapine-responsive and clozapine-resistant schizophrenia.

BACKGROUND: Between 25% and 50% of patients suffering from treatment-resistant schizophrenia fail to achieve a clinical response with clozapine. The rapid identification and treatment of this subgroup of patients represents a challenge for healthcare practice. AIMS: To evaluate the relationship between metabolic alterations and the clinical response to clozapine. METHODS: A multicenter, observational, case-control study was performed. Patients diagnosed with schizophrenia treated with clozapine were eligible (minimum dose 400 mg/d for at least 8 weeks and/or clozapine plasma levels ⩾ 350 µg/mL). According to the Positive and Negative Syndrome Scale (PANSS) total score, patients were classified as clozapine-responsive (CR) (<80 points) or clozapine non-responsive (CNR) (⩾80 points). Groups were compared based on demographic and treatment-related characteristics, together with body mass index (BMI), waist circumference, insulin, leptin, and C-reactive protein plasma levels. Plasma levels of clozapine and its main metabolite, nor-clozapine, were measured in all the participants. In addition, the potential relationship between PANSS scores and leptin or insulin plasma levels was assessed. RESULTS: A total of 46 patients were included: 25 CR and 21 CNR. BMI and waist circumference, fasting insulin and leptin plasma levels were lower in the CNR group, while C-reactive protein was not different. Moreover, significant negative correlations were observed between PANSS positive and general psychopathology subscores, on one hand, and insulin and leptin plasma levels, on the other hand, as well as between PANSS negative subscores and leptin plasma levels. CONCLUSIONS: Our results suggest that the lack of metabolic effect induced by clozapine is associated with the lack of clinical response.

[Argentine consensus on the diagnosis and therapeutics of treatment resistant schizophrenia]. / Consenso argentino sobre diagnóstico y tratamiento de la esquizofrenia resistente al tratamiento.

Approximately 30% of people with schizophrenia fail to respond to first-line antipsychotic treatment which impacts the burden of the disease. Treatment-resistant schizophrenia (TRS) denotes patients with failure to respond to at least two adequate trials of different antipsychotics. Clozapine is a unique drug approved for treating treatment-resistant schizophrenia, however 1/3 of patients fail to respond to clozapine. Even though different strategies have been proposed for treating clozapine-resistant schizophrenia, the evidence is very limited, unclear, and of poor quality. A formal literature search was conducted and then, panel members were asked to complete 35 questions addressing different aspects of TRS. A modified Delphi method was used to unify expert opinion and achieve consensus. The expert consensus in diagnostic and treatment of TRS is the result of experts from the main national scientific societies under the organization of the Argentine Association of Biological Psychiatric (AAPB). The consensus statement aims to guide on diagnosis and treatment.

[Approaches for the treatment of people with schizophrenia that do not respond to clozapine or ultra-resistant schizophrenia. Review of the evidence.] / Abordajes para el tratamiento de la esquizofrenia que no responde a la clozapina o esquizofrenia ultrarresistente: revisión de la evidencia.

30% of people with schizophrenia do not respond to antipsychotics. In these cases, treatment with clozapine is indicated, but only 40% of this subpopulation responds to treatment, thus forming a subgroup of resistant patients who do not respond to clozapine and are therefore referred to as ultra-resistant. Between 12 and 20% of people with schizophrenia are ultra-resistant. The objective of this work is to review the possible treatment for ultra-resistance and its scientific evidence. From the review carried out, it is clear that: 1) The addition of a second antipsychotic to clozapine has a partial response, and there is no antipsychotic that shows significant difference compared to others. 2) Of the antiepileptics, the one that generates a slight clinical improvement is sodium valproate, but even so, a complete response is not achieved. Lamotrigine, in turn, generates a therapeutic response in studies with mild to moderately symptomatic patients. 3) The use of inhibitors of d-amino oxidase, such as sodium benzoate, only achieved a slight clinical improvement without achieving a comprehensive therapeutic response. 4) The addition of memantine was not effective. 5) The addition of electroconvulsive therapy generates significant therapeutic response in severely symptomatic patients for both the positive and negative symptomatic dimensions. Electroconvulsive therapy does not generate cognitive alterations, produces improvement in immediate and long-term verbal memory and in executive functions. Currently more robust evidence concerning therapeutic approaches to ultrarresistant schizophrenia are lacking. In particular, randomized and controlled studies with significant number of patients will be valuable of help to make decisions in this subpopulation with an important impairment in their functionality and quality of life.

[Schizophrenia and antipsychotics: Metabolic alterations and therapeutic effectivity]. / Esquizofrenia y antipsicóticos: alteraciones metabólicas y efectividad terapéutica.

Schizophrenia presents a high predisposition to present metabolic alterations. This is evidenced in patients never treated with antipsychotics (naïve) and first-degree relatives who do not have the disease, both groups have alterations in the glucose tolerance curve, increase in basal insulin, inflammatory factors and adiponectin (APN). In schizophrenics, antipsychotics increase the frequency of appearance of obesity and metabolic syndrome. These changes are accompanied by a decrease in APN and increase in leptin. Hypertriglyceridemia and hypercholesterolemia correlates with the activation of transcription factor SCREBP1 and 2, in a dose and time dependent manner. The activation of SCREBP increases the expression of enzymes that synthesize triglycerides and cholesterol. There is a strong correlation between the appearance of metabolic alterations and response to treatment in all antipsychotics, this is more evident with clozapine and olanzapine. This relationship between the metabolic effect of the antipsychotic and the effectiveness of the treatment could be related, directly, with the inhibition of GSK3ß produced by the antipsychotics.