Antipsychotic-associated Metabolic and Cardiovascular Risks

Patients with major psychiatric disorders are at high-risk for cardio-metabolic disruptions. These disruptions are attributable to multiple factors, including genetic predisposition, developmental and environmental stressors, and lifestyle.¹ Use of antipsychotic medication in the treatment of these disorders compounds this risk. Although suicide is a risk in psychiatric patients, the leading cause of death in patients with schizophrenia or bipolar disorder is cardiovascular disease (CVD).² Despite the availability of expert consensus guidelines for screening, monitoring, and management of metabolic problems in these patients, reports show that many patients continue to receive substandard care in this regard.¹ This column reviews the effects of atypical antipsychotics, also known as second-generation antipsychotics (SGAs), on metabolic parameters, and guides NPs in monitoring and minimizing complications associated with use of these medications.

Second-generation Antipsychotics

Second-generation antipsychotics (SGAs) such as risperidone and olanzapine have largely replaced first-generation antipsychotics (FGAs) such as chlorpromazine and haloperidol in the treatment of psychotic disorders.³ This transition has occurred over many years, with data showing similar efficacy between the two groups of agents and few or no acute extrapyramidal symptoms (eg, dystonia) with therapeutic SGA dosages.^3,4 That is, although no absolute criterion distinguishes SGAs from FGAs, the major advantage of SGAs appears to be their ability to produce an antipsychotic response with a lower risk for neurologic side effects, particularly those involving movement.^4,5 

Second-generation antipsychotics are used not only as the mainstay of therapy for schizophrenia, but also as treatment for bipolar disorder, for treatment-resistant major depressive disorder (MDD), as adjunctive treatment for MDD, and for irritability symptoms of autistic disorder.³  With the increasingly widespread use of SGAs, clinicians are facing more and more cases of SGA-associated disruptions in metabolic function manifested by weight gain, dyslipidemia, and hyperglycemia, including new-onset type 2 diabetes mellitus (DM). According to Hasnain et al,¹ these metabolic disturbances are all risk factors for CVD. These risk factors, in conjunction with lifestyle and genetic components, contribute to the decreased lifespan of patients with schizophrenia.^1,3 

Nurse practitioners treating patients with antipsychotics in primary care settings, residential settings for the developmentally disabled, psychiatric facilities, or long-term care facilities, need to assess patients comprehensively for these CVD risk factors. In addition, NPs need to inform patients and/or their caregivers of the risks and benefits of SGA therapy, which will vary for each individual patient.³

Weight gain is a common major side effect of antipsychotics in both adults and children.6,7 Table 1 provides a comparison of the relative incidence of weight gain associated with each SGA.^1,4,8  Olanzapine and clozapine cause more weight gain than do the other SGAs (>7% of baseline body weight in ≥40% of patients).^4,6,9 Ziprasidone and aripiprazole are associated with minimal weight gain.⁴

Elevations in serum triglycerides (TG) and cholesterol have been reported with at least some of the SGAs.⁴ A relatively lower risk for change in serum lipid levels has been reported for risperidone, ziprasidone, and aripiprazole.^1,8,10 Risks for the development of metabolic syndrome (elevations in blood glucose [BG], TG, weight, abdominal circumference, and blood pressure [BP] and a reduction in high-density lipoprotein cholesterol) and DM associated with SGA use warrant a general health screening and ongoing monitoring. Table 2 summarizes recommended monitoring parameters for SGA users. If abnormalities occur, intervention must be prompt (see Reducing SGA-related Metabolic Complications).^11,12

Second-generation antipsychotics cause adverse cardiovascular effects such as electrocardiographic (ECG) changes and orthostatic hypotension (OH).⁴ ECG changes may include tachycardia secondary to anticholinergic effects or reflex tachycardia secondary to alpha-adrenergic blockade; flattened T waves; ST-segment depression; and prolongation of the QT and PR intervals.⁴ OH may result when antipsychotics block beta-adrenergic receptors, and can lead to falls and fractures, especially in the elderly.¹³ OH is most likely to occur with low-potency FGAs such as chlorpromazine and thioridazine and with SGAs such as clozapine, risperidone, olanzapine, and quetiapine.^4,13 These agents must be used with caution in seniors with pre-existing CVD or cerebrovascular disease, and in persons taking diuretics or concomitant medications that can prolong the QTc interval. Examples of medications that prolong the QT interval include macrolides (eg, erythromycin, clarithromycin, azithromycin), fluoroquinolones (eg, levofloxacin, moxifloxacin), antiarrhythmics (eg, quinidine, disopyramide, amiodarone), and the antifungals ketoconazole and voriconazole.^4,9 Antipsychotics most likely to cause ECG changes are thioridazine, clozapine, and ziprasidone.4 In patients >50 years old, a baseline ECG and measurement of baseline serum potassium and magnesium levels are recommended.⁴ 

Monitoring—Before initiation of SGA therapy, patients are screened for DM, hypertension (HTN), dyslipidemia, and family history of CVD. This comprehensive screening includes these parameters: weight, waist circumference, BP, fasting plasma glucose, and fasting lipid panel.¹²

Published guidelines support the measurement of fasting plasma glucose or HbA1C to monitor blood sugar.^14,15 Monitoring recommendations for patients receiving SGAs are provided in Table 2, as per expert consensus.¹² According to published recommendations, if BG and BP remain normal from baseline to 12 weeks, then they may be monitored annually thereafter. A normal lipid profile from baseline through 12 weeks warrants a lipid profile every 5 years thereafter. For patients who present with abnormal BG or lipid levels, further evaluation is recommended even if they are asymptomatic.¹² Trial of alternative SGAs not associated with significant weight gain, referral for evaluation by a clinician with experience treating persons with diabetes. All patients with DM should be referred to an American Diabetes Association-recognized diabetes self-management education program if available. These patients should carry diabetes identification.

Risk Minimization and Management Strategies—Physical activity and nutrition counseling are recommended for all patients initiated on SGAs associated with significant weight gain and for overweight/obese patients prior to initiation of SGA therapy.12,16 Switching to an SGA associated with less weight gain is considered if a patient’s total body weight increases ≥5% from baseline after initiation of the original SGA.12 

A trial of aripiprazole or ziprasidone is recommended as initial therapy, when possible, in patients who are overweight or who have DM or DM risk factors; compared with other SGAs, these two agents have been shown to cause less weight gain, dyslipidemia, and glucose intolerance/type 2 DM.^12,16 If patients experience dyslipidemia, hyperglycemia, or glucose intolerance while using an SGA, therapy is changed to an alternative agent.^4,12,16,17 Because switching antipsychotics may precipitate a loss of symptom control, care is exercised in weighing the benefit of therapy against the potential for metabolic derangements.^8,18 Of note, experts recommend that, when switching agents, prescribers cross-titrate them as opposed to abruptly stopping one and starting another (log on to http://care.diabetesjournals.org/content/27/2/596.full for more information).¹²

In some cases, the benefit of continuing therapy with a specific SGA outweighs the risks—despite metabolic complications. However, adding another agent will be necessary to attenuate the metabolic side effects. Before adding medication, nonpharmacologic therapy and lifestyle modifications are encouraged.³ Managing SGA-associated metabolic side effects with medication is based on available scientific evidence. A randomized controlled trial of patients with their first episode of schizophrenia showed that mean decreases in body mass index, insulin resistance index, and waist circumference achieved with metformin 750 mg/day in combination with lifestyle modifications were greater than the effects of lifestyle modifications or metformin 750 mg/day alone.¹⁹ Metformin has produced the greatest average weight loss (2.94 kg) over an average of 13 weeks, according to a meta-analysis of numerous randomized, double-blind, placebo-controlled studies examining 15 different medications used to attenuate weight gain.²⁰

Specific guidelines were published recently regarding the use of metformin in managing SGA-induced weight gain and glucose-metabolism dysregulation (see reference 21).^2,21 If metabolic abnormalities progress to the level of a disorder such as DM or HTN, NPs need to use established guidelines, such as those of the American Diabetes Association or the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, to target to therapeutic goal and treat the disorder.²²

Nursing Interventions

Psychosis has a high potential to become chronic, often requiring long-term SGA therapy.²³ Nursing interventions for patients treated with antipsychotics include care assessment, planning, and evaluation with regard to risk minimization strategies.²³ These interventions are especially important in seniors, who, compared with younger patients, experience more adverse effects with psychoactive medications, with a tendency toward greater severity.¹³