clozapine and Diabetic-Ketoacidosis

Second generation antipsychotics (SGAs) are associated with metabolic disturbances. Diabetic ketoacidosis (DKA) is a rare, but potentially fatal sign of acute glucose metabolism dysregulation linked to the use of SGAs. The aims of this article are to present patients with a history of psychotic disorders and of severe metabolic diabetic ketoacidosis, possibly associated with the use of antipsychotics, and to review the current literature on the topic of antipsychotic-induced DKA.. PubMed/Medline and EBSCO databases were searched using the keywords: diabetic ketoacidosis, antipsychotics, atypical antipsychotics, second generation antipsychotics, clozapine, olanzapine, risperidone, quetiapine, ziprasidone, aripiprazole, paliperidone, amisulpride and haloperidol. Case reports, case series and reviews of case series were included in the review.. The majority of patients who developed DKA following treatment with antipsychotics were treated with olanzapine and clozapine in monotherapy or in combination with other antipsychotics. DKA mostly occurred in the first six months of antipsychotic treatment. Other risk factors included insulin resistance prior to antipsychotic treatment, male gender and middle age.. Clinicians should consider the risk of DKA when starting treatment with SGAs. Preventive measures for patients with psychotic disorders using antipsychotics should include regular assessment of risk factors and screening for diabetes before and after administering antipsychotics, especially in the first months of treatment. Whenever possible, polypharmacy should be avoided.

Topics: Adolescent; Adult; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Clozapine; Diabetic Ketoacidosis; Drug Therapy, Combination; Female; Haloperidol; Humans; Insulin; Male; Middle Aged; Olanzapine; Psychotic Disorders; Schizophrenia; Schizophrenic Psychology; Young Adult

Patients exposed to second-generation antipsychotics (SGAs) have approximately 10 times increased risk of diabetic ketoacidosis (DKA) compared with the general population. However, as DKA is a rare complication of type 2 diabetes mellitus, and susceptible patients exposed to antipsychotics may rapidly develop DKA independently of treatment duration and weight gain, this is rather suggestive of type 1 diabetes mellitus (T1DM) or latent autoimmune diabetes in adults.. We performed a systematic review of current studies regarding antipsychotic-associated DKA with type 1 etiology and analyzed Danish adverse drug event (ADE) reports (previously unpublished cases).. PubMed, Embase, and the Cochrane Library were searched for all relevant studies, and the Danish Medicines Agency retrieved ADE reports using the Danish ADE database (up to date as of June 28, 2016). Diagnosis of antipsychotic-associated DKA with type 1 etiology was either considered confirmed or possible depending on authors' conclusions in the studies and/or clinical aspects. In addition, clinico-demographic risk factors were extracted.. A total of 655 records and 11 ADE reports were identified, and after screening for eligibility, we included 21 case reports/series and two ADE reports (n = 24). No relevant clinical studies were included. Although fatal cases were identified, these were excluded because of diagnostic uncertainties (n = 15). DKA occurred in 15 males (62.5 %) and nine females (37.5 %), with a mean age ± standard deviation of 34.8 ± 12.4 years. Median time to DKA was 5 months (interquartile range: 1.4-11 months). Associated antipsychotics were olanzapine (n = 9, 36 %), aripiprazole (n = 6, 24 %), risperidone (n = 6, 24 %), clozapine (n = 3, 12 %), and quetiapine (n = 1, 4 %). Nine patients (37.5 %) were confirmedly diagnosed with T1DM following DKA resolution, whereas 15 patients (62.5 %) had possible T1DM. In 22 patients (91.7 %), ongoing insulin treatment was required for glycemic control.. Increased awareness of the potential risk of antipsychotic-associated DKA and subsequent T1DM diagnosis, with insulin requirements for glycemic control, is warranted. The underlying mechanisms are poorly understood but most probably multifactorial. Certainly, further studies are warranted. Clinicians must utilize appropriate monitoring in susceptible patients and consider the possibility of continuing antipsychotic treatment with appropriate diabetic care.

Topics: Adult; Antipsychotic Agents; Aripiprazole; Benzodiazepines; Blood Glucose; Clozapine; Denmark; Diabetes Mellitus, Type 1; Diabetic Ketoacidosis; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Hypoglycemic Agents; Insulin; Male; Middle Aged; Olanzapine; Risk Factors; Risperidone; Young Adult

Clozapine is the preferred option for treatment-resistant schizophrenia. However, since 1975, clozapine has been known to cause agranulocytosis. In the clozapine screening guidelines, white blood cell count is mandatory. In the past 20 years, after its reintroduction, 3 other serious side effects, namely, diabetic ketoacidosis, gastrointestinal hypomotility, and myocarditis have been documented but have so far failed to be incorporated in the screening guidelines. The objective of this review is to determine whether an update of the screening guidelines for serious side effects with clozapine is evidence based.. The English-language literature, available via MEDLINE or PubMed, on the incidence of 4 clozapine-related side effects, using clozapine, agranulocytosis, diabetic ketoacidosis, and gastrointestinal hypomotility as keywords, that have been published over the period 1976-2010, was collected.. 16 studies that provided incidence rates or data from which these rates could be calculated were included.. We compared 1-year incidence rates, mortality rates in the whole study population and in the affected cases. When rates reflected longer periods of observation, the given rate was recalculated to obtain a 1-year incidence rate.. The incidence of clozapine-induced agranulocytosis varies between 3.8‰-8.0‰. The mortality rate is 0.1‰-0.3‰, and the case-fatality rate is 2.2‰-4.2‰. In diabetic ketoacidosis, the incidence was calculated at 1.2‰-3.1‰, and the case-fatality rate was 20%-31%. In gastrointestinal hypomotility, the incidence was 4‰-8‰, and the case-fatality rate was 15%-27.5%. The discrepancy in incidence rates between Australia (7‰-34‰) and the rest of the world (0.07‰-0.6‰) impairs a general approach of this side effect.. In 2 of the 3 studied side effects, diabetic ketoacidosis and gastrointestinal hypomotility, reduction of mortality to the level of agranulocytosis is both necessary and feasible. In order to obtain this outcome, the screening guidelines need to be modified; early detection of treatment-emergent hyperglycemia, that might-via diabetes mellitus-develop into diabetic ketoacidosis, requires obligatory monthly measurement of fasting plasma glucose. To prevent gastrohypomotility, and complications therefrom, the clinician should be required to choose between either weekly monitoring or standard coprescription of laxatives for prevention. The reported incidence of myocarditis (high in Australia, low in the rest of the world) is too divergent to allow for an overall recommendation outside Australia.

Topics: Agranulocytosis; Clozapine; Constipation; Diabetic Ketoacidosis; Humans; Incidence; Leukocyte Count; Mass Screening; Myocarditis; Practice Guidelines as Topic

Since the introduction of atypical antipsychotic medications, starting with clozapine in 1990, many studies have associated these drugs with the development of diabetes among other metabolic disorders, as well as with the onset of the disease as ketoacidosis. We report the case of a 28-year-old patient with schizophrenia who was admitted with diabetic acidosis 1 month after the beginning of clozapine therapy. No weight gain was reported and the patient maintains satisfactory glycemia levels with no treatment required after discontinuation of the drug. The literature on this subject and cases reported so far are reviewed, including the association of other atypical antipsychotic drugs also involved in endocrine disorders. The objective of this report is to raise the awareness of physicians treating psychiatric patients to the possibility of new-onset diabetes during therapy with atypical antipsychotic drugs and to emphasize the necessity for increased vigilance and close metabolic follow-up of these patients.

Topics: Antipsychotic Agents; Body Mass Index; Clozapine; Diabetic Ketoacidosis; Female; Humans; Male

The use of atypical antipsychotic agents is associated with the induction of both an indolent progression to insulin-resistant diabetes and an idiosyncratic beta-cell toxicity presenting as diabetic ketoacidosis, both of which are usually reversible or improved subsequent to cessation of treatment. The underlying mechanisms are unclear at present. Nonetheless, in light of the now numerous reports on the adverse metabolic effects of these drugs, the Consensus Development Conference which met in November 2003 recommends that metabolic risks be considered when starting atypical antipsychotic drugs. Their operative checklist includes baseline screening of candidates for antipsychotic treatment, which includes personal/family history of diabetes, weight, waist circumference, blood pressure, fasting plasma glucose and fasting lipid profile, and then follow-up of these parameters. Furthermore, the health professionals, patients, family and caregivers should be aware of the signs and symptoms of diabetes, especially when acute decompensation occurs which is commensurate with diabetic ketoacidosis. We wish, through this short report, to raise the awareness of physicians treating psychiatric patients to the possibility of new-onset diabetes during therapy with atypical antipsychotic drugs and to emphasize the necessity for increased vigilance and close metabolic follow-up of these patients. Moreover, the choice of the best antipsychotic treatment for each patient should take into consideration the diabetogenic effect of the different treatment options as well the other side effects.

Topics: Antipsychotic Agents; Benzodiazepines; Clozapine; Diabetes Mellitus; Diabetic Ketoacidosis; Female; Glucose; Humans; Male; Olanzapine; Risperidone; Schizophrenia

Hyperglycaemia is known occasionally to occur with conventional neuroleptics, but has more recently been associated with atypical antipsychotics especially clozapine and olanzapine. This article examines more closely this association. A review of relevant published literature from 1970 to date was undertaken following Medline and Embase searches in June 2000. Hyperglycaemia with clozapine was widely reported: spontaneous reports of either hyperglycaemia or ketoacidosis were described in a total of 17 people. In a five-year naturalistic study, 30.5% of patients taking clozapine were eventually diagnosed with Type 2 diabetes. With olanzapine, a total of 10 cases of hyperglycaemia and 5 cases of ketoacidosis have been published. Reports of hyperglycaemia with other atypicals are relatively scarce. The association of hyperglycaemia or ketoacidosis with clozapine and olanzapine appears to be a true drug-induced effect. Risk factors may include male gender, age of around 40 years and being non-Caucasian. The management of hyperglycaemia depends on the causative agent. With clozapine, treatment with oral hypoglycaemics has been successful. With olanzapine, other atypical antipsychotics may be considered. Blood glucose monitoring is essential for all patients starting clozapine or olanzapine.

Topics: Adult; Age Factors; Antipsychotic Agents; Benzodiazepines; Clozapine; Diabetes Mellitus, Type 2; Diabetic Ketoacidosis; Female; Humans; Hyperglycemia; Male; Olanzapine; Pirenzepine; Racial Groups; Sex Factors

Clozapine remains the most effective agent for treatment-resistant patients with schizophrenia. Recently, treatment with clozapine has been linked to a number of metabolic disturbances, including weight gain, diabetes mellitus, and serum lipid abnormalities. Despite the potential risks of medical morbidities, clozapine continues to have a major role in the care of treatment-resistant patients with schizophrenia. This article discusses the diagnosis and significance of the above metabolic abnormalities and potential mechanisms for these abnormalities as well as recommendations for monitoring and treatment.

Topics: Cholesterol; Clozapine; Diabetes Mellitus; Diabetes Mellitus, Type 2; Diabetic Ketoacidosis; Glucose Tolerance Test; Humans; Hyperlipidemias; Hypertriglyceridemia; Schizophrenia; Weight Gain

Type 2 diabetes (T2D) and raised blood lipids are associated with the use of antipsychotics, not least clozapine.. To describe the prevalence of high blood glucose levels, T2D, and dyslipidemia, in association with the use of clozapine or other antipsychotics in patients with schizophrenia in Iceland.. This study identified 188 patients treated with clozapine and 395 patients never treated with clozapine by searching the electronic health records of Landspitali, the National University Hospital. The comparison group consisted of Icelandic population controls. Data were obtained on blood glucose, HbA1c, and blood lipid levels from these health records.. The prevalence of T2D was 14.3% in the clozapine group, where the mean age was 51.2 years, and 13.7% in the never-on-clozapine group, where the mean age was 58.6 years. Males on clozapine were 2.3-times more likely and females 4.4-times more likely to have developed T2D than controls from an age-adjusted Icelandic cohort, while males on other antipsychotics were 1.5-times more likely and females 2.3-times as likely to have T2D than controls. Only one case of ketoacidosis was identified. Triglyceride levels were significantly higher in both treatment groups compared to controls in the age-adjusted Icelandic cohort.. Clinicians must take active steps to reduce the risk of T2D and raised triglycerides in patients with schizophrenia. Antipsychotics were associated with a greater risk of T2D developing in females compared to males.

Topics: Adult; Antipsychotic Agents; Blood Glucose; Case-Control Studies; Clozapine; Cohort Studies; Diabetes Mellitus, Type 2; Diabetic Ketoacidosis; Dyslipidemias; Female; Humans; Iceland; Lipids; Male; Middle Aged; Prevalence; Risk; Schizophrenia; Sex Factors

The atypical antipsychotic agent clozapine, although an effective treatment for schizophrenia, is linked with metabolic adverse effects. We report a case of diabetic ketoacidosis and very severe hypertriglyceridaemia associated with clozapine use, in a patient with type 2 diabetes mellitus, who was successfully treated with continuous insulin infusion and fluids. As clozapine proved to be the most efficacious in controlling the patient's psychotic symptoms, the patient has been continued on clozapine despite its known metabolic side effects. Importantly the patient has achieved satisfactory long-term lipid and glycaemic control. The current recommendations related to the metabolic care for patients treated with atypical antipsychotic agents as well as the mechanisms behind abnormal glucose and lipid regulation with clozapine therapy are discussed.

Topics: Adult; Antipsychotic Agents; Clozapine; Diabetes Mellitus, Type 2; Diabetic Ketoacidosis; Fluid Therapy; Humans; Hypertriglyceridemia; Hypoglycemic Agents; Infusions, Intravenous; Insulin; Male; Psychotic Disorders; Treatment Outcome

Topics: Antipsychotic Agents; Clozapine; Constipation; Diabetic Ketoacidosis; Humans; Mass Screening; Myocarditis; Practice Guidelines as Topic

Mortality in schizophrenic patients is clearly higher than in the general population. One of the reasons is the higher prevalence of the lethal side-effects of antipsychotics: diabetic ketoacidosis, prolonged qt-c time and gastro-intestinal hypomotility associated with clozapine are three serious side-effects which sometimes prove fatal. Systematic screening, however, means that sideeffects can be diagnosed at an earlier, less severe stage, leading to higher rates of survival and remission. This should contribute to a normalising of the mortality rate.

Topics: Antipsychotic Agents; Clozapine; Diabetic Ketoacidosis; Gastrointestinal Motility; Humans; Long QT Syndrome; Risk Assessment; Schizophrenia

Clozapine is an effective antipsychotic drug for the treatment of therapy-resistant schizophrenia. Mandatory screening of white blood cells is a safety measure for the early detection of agranulocytosis caused by treatment with clozapine. However, so far, there is no standard screening for two other potentially lethal side-effects, namely diabetic ketoacidosis and gastro-intestinal hypomotility. The current situation is weighed up on the basis of a comparison of the chances that these side-effects can occur and cause death. The conclusion is that weekly or monthly screening should be carried out for all these side-effects.

Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Diabetic Ketoacidosis; Gastrointestinal Motility; Humans; Leukocyte Count; Schizophrenia

Topics: Akathisia, Drug-Induced; Alcoholism; Antipsychotic Agents; Aripiprazole; Clozapine; Cocaine-Related Disorders; Comorbidity; Delayed-Action Preparations; Diabetic Ketoacidosis; Drug Therapy, Combination; Female; Humans; Injections, Intramuscular; Middle Aged; Molindone; Piperazines; Quinolones; Schizophrenia, Paranoid; Substance Withdrawal Syndrome

Topics: Antipsychotic Agents; Aripiprazole; Benzodiazepines; Clozapine; Diabetes Mellitus; Diabetic Ketoacidosis; Dibenzothiazepines; Humans; Mass Screening; Olanzapine; Piperazines; Predictive Value of Tests; Prospective Studies; Quetiapine Fumarate; Quinolones; Severity of Illness Index

The purpose of the study was to determine the proportion of patients with schizophrenia with a stable regimen of antipsychotic monotherapy who developed diabetes or were hospitalized for ketoacidosis.. Patients with schizophrenia for whom a stable regimen of antipsychotic monotherapy was consistently prescribed during any 3-month period between June 1999 and September 2000 and who had no diabetes were followed through September 2001 by using administrative data from the Department of Veterans Affairs. Cox proportional hazards models were developed to identify the characteristics associated with newly diagnosed diabetes and ketoacidosis.. Of the 56,849 patients identified, 4,132 (7.3%) developed diabetes and 88 (0.2%) were hospitalized for ketoacidosis. Diabetes risk was highest for clozapine (hazard ratio=1.57) and olanzapine (hazard ratio=1.15); the diabetes risks for quetiapine (hazard ratio=1.20) and risperidone (hazard ratio=1.01) were not significantly different from that for conventional antipsychotics. The attributable risks of diabetes mellitus associated with atypical antipsychotics were small, ranging from 0.05% (risperidone) to 2.03% (clozapine).. Although clozapine and olanzapine have greater diabetes risk, the attributable risk of diabetes mellitus with atypical antipsychotics is small.

Topics: Ambulatory Care; Antipsychotic Agents; Benzodiazepines; Clozapine; Diabetes Mellitus; Diabetic Ketoacidosis; Dibenzothiazepines; Hospitalization; Humans; Incidence; Olanzapine; Proportional Hazards Models; Quetiapine Fumarate; Risk Factors; Risperidone; Schizophrenia; United States

Information from the Ohio Department of Mental Health (ODMH) database was reviewed retrospectively to identify patients at the Cincinnati center treated with an atypical antipsychotic and who had also been evaluated or treated for diabetes mellitus. Blood glucose levels, glucose tolerance, or other evaluations of diabetes had been conducted in 14 of the 126 patients treated with atypical antipsychotics. In 11 of the 14, new-onset, acute, and marked glucose intolerance developed after treatment with clozapine, olanzapine or quetiapine. Of these, six patients required insulin therapy (four only transiently) and five patients developed diabetic ketoacidosis (DKA). Also, glucose metabolism was labile in all cases, and was transient in two cases with subsequent resolution despite on-going antipsychotic therapy. Certain atypical antipsychotics may be associated with new-onset glucose intolerance, including acute diabetes and ketoacidosis. Monitoring for changes in blood glucose levels in patients taking atypical antipsychotics may be indicated. More systematic study data are clearly needed.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Clozapine; Diabetes Mellitus; Diabetic Ketoacidosis; Dibenzothiazepines; Female; Humans; Male; Middle Aged; Ohio; Olanzapine; Pirenzepine; Quetiapine Fumarate; Retrospective Studies

We report a case of diabetic ketoacidosis in a 54-year-old white female with type 2 diabetes and schizophrenia during clozapine treatment.

Topics: Antipsychotic Agents; Clozapine; Diabetes Mellitus, Type 2; Diabetic Ketoacidosis; Female; Humans; Middle Aged; Schizophrenia

Topics: Adult; Antipsychotic Agents; Cause of Death; Clozapine; Cross-Sectional Studies; Diabetic Ketoacidosis; Female; Humans; Incidence; Long-Term Care; Male; Maryland; Middle Aged; Schizophrenia

Topics: Adult; Antipsychotic Agents; Bipolar Disorder; Black People; Blood Glucose; Clozapine; Diabetic Ketoacidosis; Drug Interactions; Fatal Outcome; Humans; Hyperglycemia; Male; Risk Factors

Topics: Adult; Anticonvulsants; Antipsychotic Agents; Carnitine; Clozapine; Coma; Diabetic Ketoacidosis; Drug Interactions; Humans; Hyperammonemia; Male; Valproic Acid

To describe the fifth case of clozapine-induced diabetic ketoacidosis (DKA) with complete resolution of abnormal glucose metabolism after discontinuation of clozapine as assessed by oral glucose tolerance testing (OGTT) and the first to be serially studied with markers of pancreatic autoimmunity; to demonstrate insulin resistance using the euglycemic clamp study and reduced pancreatic insulin reserve using intravenous glucose tolerance testing (IVGTT) in clozapine-induced diabetes mellitus and DKA, when the OGTT was normal; and to systematically review the previously described cases of clozapine-induced diabetes mellitus and DKA.. A 33-year-old white man without past or family history of diabetes mellitus presented with DKA after eight months of clozapine therapy (50 mg twice daily). After treatment of DKA and discontinuation of clozapine, glucose tolerance and concurrent serum insulin concentrations reverted to normal as measured by two OGTT performed 60 and 320 days after resolution of DKA.. Antiislet-cell antibodies, antiglutamic acid decarboxylase antibodies, and human insulin antibody were negative on two separate occasions. Euglycemic clamp study demonstrated insulin resistance manifested by a glucose disposal rate of approximately 55% of mean normal values. IVGTT demonstrated a low rate of glucose disappearance (KG = 0.95) and diminished first-phase insulin response when OGTT was normal, indicating impairment in insulin sensitivity and reduction in beta cell function 323 days after discontinuance of clozapine. This adverse reaction is considered probable according to the Naranjo probability scale.. The occurrence of cases of DKA and new or worsening diabetes mellitus in patients using clozapine suggests a causal relationship. We hypothesize that the mechanism by which clozapine may produce glucose intolerance may require a preexisting latent defect in insulin secretion and insulin action. With the administration of clozapine, some of these patients may develop worsening insulin resistance and may fail to mount an appropriate compensatory beta cell insulin secretion for the degree of insulin resistance. As a consequence, hyperglycemia develops and its persistence results in glucose toxicity, further suppressing beta cell insulin secretion. Such combined defects in insulin secretion and sensitivity are known to be synergistic, leading to the development of abnormal glucose tolerance, which can be clinically manifested as a spectrum ranging from impaired glucose tolerance through severe hyperglycemia to DKA. Patients being started on clozapine should be carefully followed for the development or worsening of diabetes mellitus, regardless of the dose of the drug.

Topics: Adult; Antipsychotic Agents; Autoimmune Diseases; Blood Glucose; Body Weight; Clozapine; Diabetic Ketoacidosis; Glucose Clamp Technique; Glucose Tolerance Test; Humans; Male; Schizophrenia, Paranoid

Topics: Adult; Antipsychotic Agents; Clozapine; Diabetic Ketoacidosis; Humans; Male; Schizophrenia

Topics: Adult; Antipsychotic Agents; Bipolar Disorder; Clozapine; Diabetic Ketoacidosis; Follow-Up Studies; Glucose Tolerance Test; Humans; Insulin; Male; Psychotic Disorders

Topics: Antimanic Agents; Antipsychotic Agents; Bipolar Disorder; Clozapine; Diabetic Ketoacidosis; Drug Therapy, Combination; Female; Humans; Middle Aged; Valproic Acid

Topics: Adult; Antipsychotic Agents; Clozapine; Diabetic Ketoacidosis; Humans; Male; Schizophrenia, Paranoid

Topics: Black or African American; Clozapine; Diabetic Ketoacidosis; Drug Therapy, Combination; Humans; Lithium Carbonate; Male; Middle Aged; Schizophrenia, Paranoid

Topics: Adult; Antipsychotic Agents; Clozapine; Diabetic Ketoacidosis; Dose-Response Relationship, Drug; Drug Administration Schedule; Humans; Male; Schizophrenia

Topics: Adult; Blood Glucose; Clozapine; Diabetes Mellitus, Type 1; Diabetic Ketoacidosis; Family; Female; Humans; Schizophrenia, Paranoid