Severe mental illness: antipsychotics
Antipsychotics are mainly used to treat schizophrenia and bipolar disorder, while some are also indicated for adjunctive use in major depressive disorder. Although second-generation (atypical) antipsychotics have demonstrated improved tolerability with respect to extrapyramidal side effects relative to first-generation (typical) antipsychotics, there is evidence that certain atypical antipsychotics are associated with an increased risk for diabetes.
Antipsychotic medication use: brief overview
Antipsychotics are the cornerstone of the pharmacological treatment of schizophrenia . Although their primary indication remains schizophrenia and schizophrenia-related disorders, most antipsychotics are now used on-label to treat a broad range of symptoms and disorders, including bipolar disorders and major depressive disorders not responding to standard antidepressant treatment. In the past decade, the use of antipsychotic medications has substantially increased, in particular among children and adolescents . Antipsychotics are arbitrarily divided into first-generation (typical) and second-generation (atypical) agents (see table 1). Although second-generation antipsychotics result in improved treatment persistence, a better prevention of relapse and a reduced risk of extrapyramidal adverse effects at clinically effective doses, they are no more effective overall than the first-generation treatments .
Diabetes risk differs for different antipsychotics
Some antipsychotic drugs have a particular propensity to induce weight gain as well as metabolic abnormalities, thereby increasing the patient's risk of obesity, insulin resistance, type 2 diabetes and associated cardiovascular morbidity. The risk of diabetes related adverse events therefore differs for individual agents. Olanzapine and clozapine, and to a lesser extent quetiapine, appear to be associated with a significant increase in the risk of diabetes . When comparing first to second-generation antipsychotics, the risk of type 2 diabetes is 1.3-fold higher in those taking second-generation antipsychotic agents than in those taking first-generation drugs . The increased relative risk of adverse cardio-metabolic side effects of antipsychotics  is especially prominent in vulnerable populations, such as patients with a first-episode psychosis, those who have not previously taken antipsychotic agents (drug-naïve patients), and children and adolescents . For example, the increased risk of diabetes associated with antipsychotic drugs seems to be greatest in patients aged 0-24 years (OR=8.9, 95% CI 7.0–11.3) versus age-matched individuals not treated with these agents . A reason is that the low background risk for diabetes at a young age  makes the diabetogenic effect of the antipsychotic drugs noticeable, whereas at an older age, the effect of the biological and behavioral risk factors becomes more pronounced than that of antipsychotic drugs.
Table 1. Relative risk for antipsychotic-induced weight gain and hyperglycemia (adapted from Ref.)
|Antipsychotic drug||Associated risk* of weight gain||Associated risk* of glucose metabolism abnormalities|
|First generation antipsychotics|
|Chorpromazine||Substantial||High (limited data)|
|Fluphenazine||Low||Low (limited data)|
|Molindone||Low||Low (limited data)|
|Pimozide||Low||Low (limited data)|
|Thioridazine||Intermediate||High (limited data)|
|Second generation antipsychotics|
|Asenapine||Low||Low (limited data)|
|Iloperidone||Intermediate||Mild (limited data)|
|Lurasidone||Low||Low (limited data)|
*Relative risk when comparing antipsychotic drugs with each other.
Potential underlying mechanisms for antipsychotic-drug-induced metabolic abnormalities
Figure 1. Pathways for antipsychotic-drug-induced metabolic abnormalitiesAs can be seen in Figure 1 (adapted from Ref. ), hyperglycemia corresponding to diabetes seems to develop both in a delayed fashion, possibly through weight gain and insulin resistance, and more acutely, through direct damage to the β cells (or other molecular pathways). In particular, reports of diabetic ketoacidosis (DKA), albeit uncommon, argue against the position that glucose dysregulation associated with antipsychotic use is related to weight gain alone. While excessive adiposity represents a significant risk factor for type 2 diabetes, this is not the case with DKA, which implies significant β cell dysfunction. DKA has been reported soon after the initiation of atypical antipsychotic treatment and in individuals who experience no significant changes in weight. These cases emphasize that weight gain cannot be used as the sole proxy for concerns regarding possible glucose abnormalities following antipsychotic medication use. The occurrence of DKA also raises questions from a mechanistic standpoint; it remains unclear whether antipsychotics impact insulin and glucose metabolism via a single or two or more distinct mechanisms (i.e., one through antipsychotic-induced weight gain and one that is independent and more acute in nature).However, since diabetes is generally a more distal, later-onset adverse effect, it is crucial to assess weight changes and, especially, metabolic consequences of antipsychotic treatment (including the different cardiovascular risk factors) to obtain a complete picture of the individual risk profiles.
Although the exact mechanisms underlying antipsychotic-induced glucose regulation remain poorly understood, it has been proposed that the heterogeneous receptor binding pharmacology differentiating the atypical agents not only from each other, but also from their more selective typical counterparts, may be implicated. Antipsychotic binding to dopaminergic, serotonergic, adrenergic, and cholinergic sites is understood to influence receptors and transporters in essential body tissues implicated in glucose metabolism.
The first hypothesis is that antipsychotic drugs contribute to weight gain and associated hyperglycemia via effects mediated by binding to the serotonergic receptors 5-HT1a and 5-HT2c . Stimulation of 5-HT1a is associated with an increase in food intake whereas stimulation of 5-HT2c is related to a decrease in food intake. Antagonism of the 5-HT2c receptor can, in turn, lead to an increase in food intake. Most second-generation antipsychotic drugs, especially clozapine and olanzapine, are potent 5-HT2c antagonists. The fact that aripiprazole and ziprasidone have only a weak association with metabolic dysregulation, despite their high affinities for 5HT2c receptors, could be explained by other receptor-specific mechanisms that potentially counterbalance inhibition of the 5HT2c receptors. For example, aripiprazole is a partial agonist of 5-HT1a receptors.
Second, blockade of the dopamine D2 receptors is another potential mechanism involved . Prolonged D2 blockade with antipsychotics may predispose to depletion of insulin granule stores and a defect in pancreatic compensation. Moreover, synergistic effects between the blockade of D2 receptors and 5-HT2a or 5-HT2c receptors might have a key role in triggering a cascade of events that lead to increased energy intake, weight gain and hyperglycemia .
Third, the affinity of, in particular, second-generation antipsychotic agents for M3 receptors also seems relevant for the glucose homeostasis, perhaps because M3 receptors control cholinergic-dependent insulin release. Muscarinic M3 receptors are found on pancreatic β cells. Some antipsychotic drugs, such as clozapine and olanzapine, might impair both cholinergic-dependent and glucose-dependent insulin secretion from pancreatic β cells. Among antipsychotic agents, a high affinity for the M3 receptor, as is seen with clozapine and olanzapine, seems to have the highest propensity to promote glucose dysregulation and type 2 diabetes mellitus. Similarly to aripiprazole, risperidone, amisulpride, lurasidone, and asenapine, which have a relatively low propensity to cause weight gain, shows no appreciable affinity for muscarinic receptors .
Next to these muscarinic, dopaminergic, and serotonergic mechanisms, the identification of genetic markers associated with antipsychotic-induced weight gain seems, in turn, to be an important predictor of an individual’s response. For example, people with schizophrenia who carry the HTR2C -759C allele are found to gain more weight or to have an increased risk for clinically significant weight gain after treatment with either clozapine or olanzapine.
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