Novel antipsychotics and new onset diabetes

Wirshing, Donna A.; Spellberg, Brad; Erhart, Stephen M.; Marder, Stephen R.; Wirshing, William C.

doi:10.1016/s0006-3223(98)00100-0

Cited by 357 publications

(202 citation statements)

References 36 publications

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“…11,21 Because atypical antipsychotic drugs generally have a higher binding affinity for 5-HT receptors than D 2 receptors (Table 1), therapeutic doses often saturate 5-HT receptors to achieve sufficient D 2 occupancy for therapeutic effect. Wirshing et al 85 have proposed a serotonergic model for clozapine and olanzapine-induced diabetes, which they based on animal models showing that 5-HT 1A antagonism decreases pancreatic b-cell responsiveness, thereby decreasing insulin secretion and increasing serum glucose levels. Work in healthy volunteers has since shown that 5-HT 2 antagonists can significantly decrease insulin sensitivity compared with placebo (P = 0.047), an effect possibly mediated by the suppression of 5-HT 2A receptor-mediated glucose uptake in skeletal muscle.…”

Section: Diabetes 62mentioning

confidence: 99%

“…Work in healthy volunteers has since shown that 5-HT 2 antagonists can significantly decrease insulin sensitivity compared with placebo (P = 0.047), an effect possibly mediated by the suppression of 5-HT 2A receptor-mediated glucose uptake in skeletal muscle. 86 It should be noted, however, that most atypical antipsychotics have stronger antagonistic effects at 5-HT 2A and 5-HT 2C than at 5-HT 1A , 85 and that 5-HT 2C antagonism is most closely correlated with an increased risk of diabetes and weight gain. 53 Consistent with this notion, 5-HT 2C knockout mice develop insulin resistance and impaired glucose tolerance and experience severe weight gain.…”

Section: Diabetes 62mentioning

confidence: 99%

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Atypical antipsychotic-induced metabolic side effects: insights from receptor-binding profiles

2007

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Atypical antipsychotic drugs offer several notable benefits over typical antipsychotics, including greater improvement in negative symptoms, cognitive function, prevention of deterioration, and quality of life, and fewer extrapyramidal symptoms (EPS). However, concerns about EPS have been replaced by concerns about other side effects, such as weight gain, glucose dysregulation and dyslipidemia. These side effects are associated with potential long-term cardiovascular health risks, decreased medication adherence, and may eventually lead to clinical deterioration. Despite a greater understanding of the biochemical effects of these drugs in recent years, the pharmacological mechanisms underlying their various therapeutic properties and related side effects remain unclear. Besides dopamine D 2 receptor antagonism, a characteristic feature of all atypical antipsychotic drugs, these agents also bind to a range of non-dopaminergic targets, including serotonin, glutamate, histamine, a-adrenergic and muscarinic receptors. This review examines the potential contribution of different receptors to metabolic side effects associated with atypical antipsychotic treatment for all seven agents currently marketed in the United States (risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole, paliperidone and clozapine) and another agent (bifeprunox) in clinical development at the time of this publication.

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Section: Diabetes 62mentioning

confidence: 99%

Section: Diabetes 62mentioning

confidence: 99%

Atypical antipsychotic-induced metabolic side effects: insights from receptor-binding profiles

2007

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“…Quetiapine was selected for studies in normal subjects based on our past experience (Wasserman et al, 2002), lack of association with rare but severe side effects observed with other atypical antipsychotics (Idanpaan-Heikkila et al, 1975;Wirshing et al, 1998), and 'clozapine-like' profile in preclinical studies of PPI (Swerdlow et al, 1994b(Swerdlow et al, , 1996. Analyses attempted to identify correlates or predictors of quetiapine effects on PPI in normal subjects with a 'low PPI' trait.…”

Section: Introductionmentioning

confidence: 99%

Antipsychotic Effects on Prepulse Inhibition in Normal ‘Low Gating’ Humans and Rats

Swerdlow

Talledo

Sutherland

et al. 2006

Neuropsychopharmacol

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Development of new antipsychotics and their novel applications may be facilitated through the use of physiological markers in clinically normal individuals. Both genetic and neurochemical evidence suggests that reduced prepulse inhibition of startle (PPI) may be a physiological marker for individuals at-risk for schizophrenia, and the ability of antipsychotics to normalize PPI may reflect properties linked to their clinical efficacy. We assessed the effects of the atypical antipsychotic quetiapine (12.5 mg po) on PPI in 20 normal men with a 'low PPI' trait, based on PPI levels in the lowest 25% of a normal PPI distribution. The effects of quetiapine (7.5 mg/kg s.c.) on PPI were then assessed in rats with phenotypes of high PPI (Sprague Dawley (SD)) and low PPI (Brown Norway (BN)); effects of clozapine (7.5 mg/kg i.p.) and haloperidol (0.1 mg/kg s.c.) on PPI were also tested in SD rats. At a time of maximal psychoactivity, quetiapine significantly enhanced PPI to short prepulse intervals (20-30 ms) in 'low gating' human subjects. Quetiapine increased PPI in low gating BN rats for prepulse intervals o120 ms; this effect of quetiapine was limited to 20 ms prepulse intervals in SD rats, who also exhibited this pattern in response to clozapine but not haloperidol. In both humans and rats, normal 'low gating' appears to be an atypical antipsychotic-sensitive phenotype. PPI at short intervals may be most sensitive to pro-gating effects of these drugs.

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“…Studies have shown, for example, that hyperglycaemia can occur without differences in weight. 15,18,19 Clozapine treatment is associated with increased insulin levels, consistent with the drug directly reducing peripheral insulin sensitivity. 17,20 Studies have therefore been carried out to investigate the interaction between atypical antipsychotics and insulin action at the molecular level.…”

mentioning

confidence: 85%

“…Antagonism of serotonin 1A receptors on pancreatic beta-cells is a possible mechanism by which this has been suggested to occur. 19 …”

Section: Possible Actions Of Atypical Antipsychotic Drugs On Beta-cellsmentioning

confidence: 99%

Atypical antipsychotic drugs and diabetes

Livingstone¹,

Rampes

2003

Pract Diab Int

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Atypical antipsychotic drugsSchizophrenia is a syndrome characterised by a broad range of cognitive, emotional and behavioural problems, the prevalence of which is estimated at 0.2-1.0% in the general population. Its symptoms are classified into positive (hallucinations, delusions, formal thought disorder and bizarre behaviour) and negative (flattening of mood, emotional apathy, social withdrawal, lack of motivation and loss of pleasure). Schizophrenia has been treated largely using conventional antipsychotic drugs. However, over the last 10 years, the atypical, also known as novel or secondgeneration, antipsychotics have increasingly been used. The British National Formulary currently lists amisulpride, clozapine, olanzapine, quetiapine, risperidone, sertindole and zotepine as atypical antipsychotic drugs. From a pharmacological perspective, they are distinguished by their dual action of serotonin 2A receptor and dopamine D2 receptor antagonism as compared to the conventional antipsychotic drugs, which have an antagonistic action mainly on the D2 receptor.The atypical antipsychotics are indicated both for the treatment of schizophrenia and related disorders in which psychosis is a defining feature. However, they can also be used to quieten patients whatever the underlying psychopathology, e.g. brain damage, severe anxiety, toxic delirium or agitated depression. From a clinical perspective, atypical antipsychotic drugs have a lower incidence of extrapyramidal adverse effects than the conventional antipsychotic drugs and are more efficacious in the treatment of negative symptoms of schizophrenia. Recently, the National Institute Clinical Excellence has published guidance on the use of atypical antipsychotic drugs for the treatment of schizophrenia. 1 It is recommended that they are used as firstline treatments for individuals with newly diagnosed schizophrenia and should also be used for those patients whose management has been unsatisfactory on conventional drugs or who have experienced unacceptable adverse effects. The following two prescribing restrictions should be noted. Sertindole is available on a named patient supply only due to its cardiac adverse effects and clozapine is restricted to individuals who are intolerant or unresponsive to conventional antipsychotic drugs. The association between atypical antipsychotic drugs and diabetesIt has long been recognised that hyperglycaemia and type 2 diabetes mellitus are more common in patients with schizophrenia than in the general population. In one recent study the prevalence of diabetes in a sample population of patients with schizophrenia was 15.8% as opposed to 3.2% in the general population. 2 Type 2 diabetes is itself becoming a commoner condition in the population as a whole.Since the introduction of the atypical antipsychotic drugs it has become apparent that their use is associated with metabolic adverse effects (Table 1) diabetes. 4 In another study, patients who already had diabetes required to be switched from an oral hypoglycaemic agent to insulin o...

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Novel antipsychotics and new onset diabetes

Cited by 357 publications

References 36 publications

Atypical antipsychotic-induced metabolic side effects: insights from receptor-binding profiles

Atypical antipsychotic-induced metabolic side effects: insights from receptor-binding profiles

Antipsychotic Effects on Prepulse Inhibition in Normal ‘Low Gating’ Humans and Rats

Atypical antipsychotic drugs and diabetes

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