The pathophysiology of DM is complicated. There are varying degrees of insulin deficiency and peripheral resistance to the action of insulin. Genetic susceptibility and environmental factors together lead to DM development. Hyperglycemia itself worsens insulin resistance leading to slow progression of DM.

Weight gain and decreased physical activity are two major risk factors that promote DM development. Among nonpsychotropic medications that cause hyperglycemia, corticosteroids are a notable example. DM is often associated with other medical conditions that increase risk for cardiovascular disease . The constellation of obesity, diabetes, hypertension, and elevated lipids is termed metabolic syndrome.

Antipsychotics, especially those with increased propensity to cause metabolic syndrome, increase risk for hyperglycemia. While much of the effect is related to development of obesity, it is thought that antipsychotics may independently impair glucose regulation. One proposed mechanism is via blocking the muscarinic pancreatic receptor. The risk is increased both for developing chronic DM and an acute hyperglycemic episode. Hyperglycemia can develop as early as within 4 weeks of starting an antipsychotic; the mean duration is about 19 weeks of exposure [2]. This acute hyperglycemic effect may also reflect unmasking of underlying susceptibility to diabetes mellitus.

The same agents that increase risk for obesity increase risk of hyperglycemia and metabolic syndrome. Clozapine and olanzapine carry the highest risk. As a group, typical antipsychotics carry an equivalent risk to atypical antipsychotics when clozapine and olanzapine are excluded from the latter group [3].

Antipsychotics are also associated with acute hyperglycemic episodes. Older age is a risk factor. In addition to clozapine and olanzapine, risperidone and quetiapine are associated with numerous cases of acute hyperglycemia [2, 4, 5]. There are rare case reports of aripiprazole and diabetic ketoacidosis.

Acute hyperglycemia occurs both as a new diagnosis and exacerbation of preexisting DM. A possible mechanism is direct toxicity to pancreatic islet cells. Patients with preexisting diabetes are placed at higher risk of serious hyperglycemia upon initiation of an antipsychotic. But hyperglycemia can occur even without any history of diabetes and has been documented in patients started on clozapine, olanzapine, quetiapine, and risperidone. It is reversible in some cases. Risk factors that could precipitate acute hyperglycemia are poor fluid intake, substance use, systemic illness, and nonadherence to insulin in those with diagnosed DM.

There is increased hyperglycemia observed with antidepressant therapy but no causal link has been established. Any psychotropic agent that induces weight gain also carries some risk of accompanying DM.

Patients with DM are usually asymptomatic for months or years before hyperglycemia becomes severe. They may then present with polyuria, polydipsia, blurred vision, and rarely polyphagia .

Acute hyperglycemia may sometimes occur as the initial manifestation of illness and patients then are acutely ill with symptoms resulting from volume depletion, electrolyte imbalance, and altered mental status.

Poorly controlled DM is associated with complications of skin changes, infections, altered peripheral sensation, visual abnormalities, kidney disease, ischemic heart disease, and stroke.

Hyperglycemia is any elevation of blood sugar above the normal range in healthy individuals. Fasting blood sugar (FBS) or glycosylated hemoglobin (HbA1c ) is used to diagnose DM. HbA1c is a measure of the percentage of glucose carried by hemoglobin and does not vary with fasting state. When HbA1c and FBS are discrepant, the higher of the two should be used (e.g., if HbA1c is in the diabetes range and FBS is in the prediabetes range, patient is considered to have DM). The random blood sugar is not as reliable a measure as FBS or HbA1c but values > 200 mg/dL are considered high.