08 - Metabolic syndrome

Metabolic syndrome

© SPMM Course observation period of at least 1 - 3 hours in a healthcare facility and to avoid driving or operating heavy machinery in the 24 hours after injection. Metabolic syndrome Metabolic syndrome is a cluster of disorders comprising obesity (central and abdominal), dyslipidaemias, glucose intolerance, insulin resistance (or hyperinsulinaemia) and hypertension. It is highly predictive of type 2 diabetes mellitus and cardiovascular disease. Diabetes Mellitus is twice as prevalent among schizophrenia cohorts than in the general population Unaffected first-degree relatives of patients with schizophrenia share a propensity for type 2 diabetes mellitus (19-30%); this suggests a genetic association between these two disorders Schizophrenia patients have 3 times greater intra-abdominal fat (IAF) than the control group, increasing the risk for metabolic syndrome. In the pre-antipsychotic era over 15% of drug-naïve individuals with first-episode schizophrenia had impaired fasting glucose levels, hyperinsulinaemia and high levels of cortisol. Both typicals and atypicals increase the risk of metabolic syndrome in schizophrenia manifold. But antipsychotics cannot explain all the metabolic dysfunctions noted in schizophrenia. The frequency of metabolic syndrome was 2-4 times higher in a group of people with schizophrenia treated with either typical or atypical antipsychotics. MOST Olanzapine / clozapine quetiapine risperidone ziprasidone aripiprazole/ lurasidone LEAST World Health Organization criteria for metabolic syndrome World Health Organization criteria for metabolic syndrome •Insulin resistance and/or impaired fasting glucose and/or impaired glucose tolerance AND two or more of the following: •Waist - hip ratio >0.90 (men), >0.85 (women) OR body mass index 30 kg/m2; •Triglyceride level 1.7 mmol/l OR high-density lipoprotein <0.9 mml/l (men), <1.0 mmol/l (women); •Blood pressure 140/90 mmHg (or treated hypertension); •Microalbuminuria. (This is not presented in some revised criteria for metabolic syndrome)

© SPMM Course In Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Schizophrenia Trial baseline data (n = 689), the metabolic syndrome was prevalent in 51.6% of female patients and 36.0% of male patients. Females with schizophrenia have a higher risk than males with schizophrenia when compared with a reference population. Mean weight increases during the first year of therapy o 12 to 14lb for clozapine (5 to 6 kg) o 15 to 26lb for olanzapine (7 to 12kg) o 6 to 12lb for quetiapine (2.5 to 5kg) o Up to 5lb for risperidone (2 to 2.5kg) o Less than 2lb for Ziprasidone and aripiprazole For patients with schizophrenia, the best-studied options for weight control include diet and exercise. But controlled behavioral programs for weight reduction in schizophrenia have high dropout rates and are not always accessible. Switch to relatively weight neutral drugs can be considered in resistant cases. CATIE summary CATIE stands for Clinical Antipsychotic Trials of Intervention Effectiveness. The study design was double-blind pragmatic RCT. 1493 patients with chronic schizophrenia (mean duration of illness = 14 years), 57 sites, 2001 to 2004 Olanzapine, quetiapine, Risperidone, ziprasidone (added later in the trial), perphenazine Primary  outcome  is  a  ‘real-world’  measure  – discontinuation for any reason, either patient-initiated or physician initiated 76% power to detect 12% difference in primary outcome Irrespective of the prescribed drug – 74% discontinued treatment in 18 months (surprisingly high despite naturalistic design). The median time to stop was 4.6 months. Olanzapine had lowest discontinuation rate (still 64%) – but highest side effect burden. 64% discontinued olanzapine; 75%, perphenazine; 82%, quetiapine; 74%, risperidone; and 79%, ziprasidone. Olanzapine caused most weight gain while quetiapine caused most anticholinergic symptoms; perphenazine had highest EPSE related discontinuation. Those who did not respond after 18 months (those who discontinued for the ineffectiveness of therapy) were re-randomised in phase 2 trial (n=99), and Clozapine was compared to other atypical agents (efficacy pathway). Clozapine had lowest discontinuation rate – median at 10 months. This time-to-discontinuation was nearly 3 times longer than time-to-discontinuation with the other SGAs. Quetiapine had comparatively less EPSEs. As a part of the phase 2 CATIE study (tolerance pathway) those who terminated phase 1  for  ‘‘intolerable  side   effects’’  (444  volunteers)  were  tested  with  olanzapine,  risperidone,  quetiapine,  or  ziprasidone. Of these treatments, olanzapine and risperidone had equivalent effectiveness, and both were better than quetiapine or ziprasidone by significant but modest margins. CATIE Controversies o Quite complicated study design and many outcomes were analysed from the dataset. o Decisions to add ziprasidone to the protocol was made after recruitment began o Perphenazine was used only in one randomized phase (phase 1) of the study generating controversy.

© SPMM Course o The decision to use double-blinded treatments decreased the resemblance of the study procedures to those of routine clinical care

The mean doses used remain controversial though it is claimed that the study was designed to be pragmatic and not purely experimental. CUtLASS summary: CUtLASS stands for Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study It is an unblinded randomised controlled trial comparing first-generation v. second-generation antipsychotics The primary outcome was the quality of life at 1 year and symptom measures were the main secondary outcome. 1, 227 people with schizophrenia who were being assessed by their clinical team for medication review because of poor response or adverse effects were randomised. The second-generation drugs were amisulpride, olanzapine, quetiapine or risperidone. The rate of follow-up interview was 81% at 1 year. The results showed no advantage of second-generation drugs in terms of quality of life or symptom burden over 1 year with those on first-generation antipsychotic doing relatively better. Participants reported no clear preference for either class of drug. The second phase - CUtLASS 2 trial was of similar design and compared clozapine with other secondgeneration drugs in 136 patients who had not responded well to two or more previous drugs. Results showed that there was a significant advantage for clozapine in symptom improvements over 1 year; moreover, patients significantly preferred it.