US Pharm. 2007;32(11):HS3-HS14.

Atipsychotic medications are the mainstays for treating a number of serious psychiatric disorders, including schizophrenia, mania, delusional disorder, and psychosis. Additionally, antipsychotics are used to treat impulse-control difficulties in pervasive developmental disorders and mental retardation, Tourette's syndrome, and delirium. First-generation antipsychotics (FGAs), or typical antipsychotics, have been available since the mid-1950s, but a number of new antipsychotic drugs, known as second-generation antipsychotics or atypical antipsychotics, were introduced in the 1990s. These newer agents have largely replaced typical antipsychotics in clinical practice.

Mechanism of Action
The exact mechanism of action of antipsychotic medications is unknown. Psychotic experiences and positive symptoms of schizophrenia, including delusions, hallucinations, hyperactivity, and thought disorders, have been linked to excess release of the neurotransmitter dopamine in the mesolimbic pathway. The mesolimbic pathway is one of the four major neural pathways where dopamine is found, and the blockage of dopamine receptors in this pathway is thought to control psychotic experiences.1 Most antipsychotic medications block D2 receptors in the dopamine pathways of the brain, particularly the mesolimbic pathways, which correlates with their therapeutic efficacy. The negative symptoms of schizophrenia include psychomotor retardation, avolition, apathy, anhedonia, attentional impairment, and decreased emotional expression. These symptoms are associated with a dopamine deficit in the medial prefrontal cortex, anterior cingulate cortex, and orbitofrontal cortex regions of the brain and also with hypodopaminergic activity in the cortical region.2 A third symptom category of schizophrenia, cognitive dysfunction, is attributed to dopamine deficiency in the dorsolateral prefrontal cortex. Impaired attention, working memory, and executive function are areas of cognition found to be abnormal in schizophrenia.2,3 Recent research into antipsychotics focuses on the relative affinity to block D2 versus 5-HT2A receptors in various regions of the brain. Current antipsychotics can be classified into different categories, as listed in TABLE 1, according to their affinity for these individual receptors.4,5

In studies of antipsychotic receptor binding in humans, FGAs have been shown to be dopaminergic antagonists with a high affinity for D2 receptors. To decrease positive psychotic symptoms, only 60% to 65% occupancy of D2 receptors is needed, but during chronic treatment with FGAs, 70% to 90% of D 2 receptors are occupied. Blockade of approximately 77% or more of D 2 receptors is associated with extrapyramidal symptoms (EPS), e.g., muscle stiffness, agitation, tardive dyskinesia, and dystonia, and those exceeding 72% are associated with a significant likelihood of serum prolactin elevation.4,6 Thus, treatment with FGAs most often exceeds the threshold for EPS and leads to hyperprolactinemia. FGAs are often referred to as typical antipsychotic medications because they commonly produce these adverse effects. Use of typical antipsychotics has narrowed considerably, but they are still common in hospital formularies. This is due to their continued use in the acute hospital setting and also because they are the only medications available for intravenous administration. Typical agents are less preferred for the long-term treatment of psychosis due to increased cumulative risk for the development of EPS, specifically tardive dyskinesia.7 For the most part, the typical antipsychotics are not thought to have mood-stabilizing properties but may be used adjunctively in the initial treatment of mood disorders when mood symptoms are accompanied by psychosis.8

Unlike typical agents, atypical antipsychotics given in dosages within the clinically effective range do not bring about EPS. Atypical antipsychotics transiently block D2 receptors and then dissociate rapidly, allowing for normal dopamine neurotransmission. This transient blockade is adequate to produce antipsychotic effects, but long-term blockade of D2 is needed for the adverse effects seen with the typical agents.8,9 Atypical antipsychotics also tend to exhibit enhanced serotonergic activity. Antagonizing the 5-HT2A receptor in combination with the modest D 2 blockade in specific regions of the brain is thought to decrease negative symptoms and improve cognition compared to typical agents. It is clear that the modulation of the dopamine in the neuronal pathways is the primary mechanism by which antipsychotics exert their benefits, but the role of the serotonergic activity of the atypicals is debated. The "atypicality" of atypical antipsychotics is thought to be due to the D2 receptor antagonism coupled with the 5-HT2A receptor antagonism.10,11 Another theory for the effectiveness of these agents, however, is the quick dissociation from the D2 receptor, allowing for better transmission of normal physiologic dopamine surges.12 Atypical antipsychotics are equally or more efficacious and better tolerated than typical agents. With the exception of clozapine, the first atypical agent with superior efficacy over all other atypical agents, there is limited evidence of superior efficacy between the remaining atypical antipsychotics. However, there is variability in adverse effects among atypical agents due to variations in their receptor-binding profiles.13

Antipsychotics and Adverse Effects
All antipsychotics vary in their effects on neurotransmitters other than D2 and 5-HT2A, including the antagonism of D1, D4 , 5-HT2C, 5-HT6, 5-HT7, muscarinic, alpha 1- and alpha2-adrenegic, and histaminic receptors. These varying effects explain the potential differences in adverse effect profiles, listed in TABLE 2.14 Atypical antipsychotics, due to their different mechanisms of action, have demonstrated several advantages over typical antipsychotics in terms of positive, negative, and cognitive symptoms and a lower propensity for extrapyramidal side effects. Despite these indisputable advantages over their earlier counterparts, atypicals have been associated with causing and exacerbating metabolic disorders, such as obesity, diabetes, and dyslipidemia.8,15

Adverse metabolic effects of antipsychotics are not a new clinical observation. The earliest reports of these adverse effects date back to the early 1950s with the typical antipsychotic chlorpromazine, and neurologic  adverse effects associated with antipsychotics, such as EPS, were discussed in the medical literature. 16 The exact mechanism for weight gain tied to antipsychotics is not known, although studies have demonstrated that weight gain with antipsychotics, particularly atypical agents, may result from antagonism of the histaminic and muscarinic receptors and blockade of the 5-HT2C receptors.1

Metabolic Syndrome
Prospective observational studies demonstrate a strong association between metabolic syndrome and the risk for subsequent development of type 2 diabetes and an increase in the risk for incident cardiovascular disease and all-cause mortality.18,19 Weight gain during antipsychotic treatment has been reported as the major reason for poor medication adherence. In 2004, the International Diabetes Federation proposed a set of metabolic syndrome criteria.20 Central obesity is an essential element of this definition, with different waist circumference thresholds set for different race/ethnicity groups. Along with an increase in waist circumference, two of the following are needed: triglycerides higher than 150 mg/dL or treatment for elevated triglycerides; HDL cholesterol lower than 40 mg/dL in men or lower than 50 mg/dL in women, or treatment for low HDL; systolic blood pressure higher than 130 mmHg, diastolic blood pressure higher than 85 mmHg, or treatment for hypertension; fasting plasma glucose higher than 100 mg/dL, or previously diagnosed type 2 diabetes.

The National Institute of Mental Health sponsored the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study, a double-blind assessment of patients in the maintenance phase of treatment for chronic schizophrenia.21 Baseline information from this study indicated that 42% of patients with schizophrenia also had metabolic syndrome. This rate is much higher than the estimated rate of metabolic syndrome, 27%, in the general population, according to the National Health and Nutrition Examination Survey of 1999–2000. 22 Most studies have shown the prevalence of diabetes and obesity in patients with schizophrenia to be 1.5 to 2 times higher than unaffected subjects.15

Adverse Effect Profiles
Currently available atypical antipsychotics in the United States include risperidone (Risperdal), clozapine (Clozaril), olanzapine (Zyprexa), quetiapine (Seroquel), ziprasidone (Geodon), and aripiprazole (Abilify). Initially, these agents were FDA-approved for the treatment of patients with schizophrenia, but most of these are also currently approved for the treatment of patients with mania as monotherapy (olanzapine, risperidone, quetiapine, and ziprasidone) and some as combination therapy (olanzapine, risperidone, and quetiapine) with lithium or valproic acid (Depacon, Depakene, Depakote).

Literature reviews for atypical antipsychotics and reports of metabolic adverse effects between individual agents vary considerably. To date, most published studies are available for clozapine, olanzapine, and risperidone, whereas the information concerning potential effects of the other atypical antipsychotics is limited. The reasons for this variability include the differences in prescription rates (risperidone and olanzapine are the two most widely prescribed agents in the U.S.), the length of time these treatments have been available (clozapine, risperidone, and olanzapine have been available the longest), and differences in the level of interest concerning metabolic adverse effects with individual agents. Fewer reports were identified for quetiapine, ziprasidone and aripiprazole--the more recently approved agents--and for zot­ epine and amisulpride, agents that are not currently released in the U.S.23-25

In 2003, the FDA required all manufacturers of atypical antipsychotics to place a warning on labels for risk of hyperglycemia and diabetes.26 Although all atypicals must carry the warning on their labeling, published studies including uncontrolled observations, large retrospective database analysis, and controlled experimental studies such as randomized clinical trials indicate that all atypicals are not equal in their metabolic effects, including weight gain, diabetes, and dyslipidemia. The relative metabolic profiles of all atypical antipsychotics are summarized in TABLE 3.24,25


Weight-Gain Studies
Weight gain is seen with most atypical antipsychotics within the first few months of therapy and may not reach a plateau even after one year of treatment.27 The consensus is that clozapine and olanzapine are associated with the greatest significant weight gain, as defined by 7% of baseline body weight, followed by risperidone and quetiapine.14 A meta-analysis completed on antipsychotic-induced weight gain found that after 10 weeks of therapy, weight gains with olanzapine and clozapine were 4.45 kg and 4.15 kg, respectively, and were greatest relative to other agents.29 In the CATIE study, olanzapine was associated with the greatest weight gain and metabolic abnormalities (increases in blood glucose, triglycerides, and cholesterol) than other medications in the study, which included all atypical antipsychotic agents. The CATIE study found that over the study period (up to 18 months), patients taking olanzapine gained an average of 2 pounds per month and 30% experienced significant weight gain. Additionally, olanzapine discontinuation was associated with weight gain and metabolic adverse effects.30 In numerous studies and meta-analyses of antipsychotic medications, clozapine has been identified as carrying the greatest risk, followed by olanzapine.29 Weight gain with clozapine and olanzapine has been shown to be independent of dosage and tends to plateau between 6 to 12 months after initiation of therapy. However, risperidone, quetiapine, and ziprasidone have been shown to reach a plateau in weight gain earlier, within the first several months of treatment.27

Data availability from clinical trials of ziprasidone and ari­ piprazole is increasing, but clinical experience with these newer agents is not as developed as with the older agents. These two agents are thought to have the smallest adverse effects on weight and glucose or lipid metabolism. In the CATIE study, ziprasidone was the only atypical agent associated with the improvement of metabolic factors. 30 In a randomized, double-blind study comparing weight gain between olanzapine and aripiprazole, significantly more patients receiving olanzapine experienced a clinically significant increase in weight.31 This finding led the study authors to conclude that aripiprazole is much less likely than olanzapine to be associated with weight gain or metabolic abnormalities.

Diabetes and Other Metabolic Abnormalities
The extent to which drug-related weight gain and increased rates of new-onset diabetes or exacerbation of diabetes in patients receiving atypical antipsychotics is not clear.32 Case reports tentatively suggest that substantial weight gain or obesity may not be a factor in up to one-quarter of cases of new-onset diabetes that occur during treatment.33 These cases may be related to the direct antagonism at the 5-HT2C or H1 receptors or to an elevation of serum leptin by certain atypical agents, beyond that induced by increased body weight alone.17

New-onset type 2 diabetes has been reported in patients treated with olanzapine, clozapine, risperidone, quetiapine, and ziprasidone. Although studies have shown that clozapine and olanzapine have the greatest risk for diabetes, there are limited data on the overall incidence and relative occurrence across atypical agents. The risk for diabetes with quetiapine and risperidone is less clear, with some, but not all, studies showing an increase in risk.32,33 Additionally, atypical antipsychotic medications have been associated with a small increased risk of diabetic ketoacidosis.34 Since ziprasidone and aripiprazole are relatively new, extended clinical experience is limited compared with other atypical antipsychotics. However, available data from clinical trial experience with these two agents do not show an increase risk of diabetes. In one recent study comparing aripiprazole and olanzapine, after 52 weeks, the mean change in patients receiving olanzapine was an increase in serum glucose levels of  12.02 mg/dL, while the mean change in patients receiving aripiprazole was a decrease of 1.44 mg/dL.35 It is likely that risk factors other than exposure to these agents, such as advancing age, family history of diabetes, ethnicity, obesity, and lack of physical exercise, play an important role.

As with diabetes, changes in serum lipid levels with atypical antipsychotics are unclear due to limited data. The available information displays a correlation between weight gain and changes in serum lipid levels.28 Clozapine and olanzapine, which exhibit the greatest weight gain, are also associated with the greatest increase in total cholesterol, triglycerides, and LDL cholesterol and with decreased HDL levels. Risperidone, ziprasidone, and aripiprazole may have the least effect on serum lipids.14 In a recent case-control study evaluating hyperlipidemia following treatment with antipsychotic medications, the odds ratio for hyperlipidemia ranged from 1.82 for clozapine to 1.26 for first-generation antipsychotics.36

Prevention and Treatment of Metabolic Adverse Events
In November 2003, the American Diabetes Association, the American Psychiatric Association, the American Association of Clinical Endocrinologists, and the North American Association for the Study of Obesity convened a consensus development conference on the subject of antipsychotic medications and diabetes and obesity.37 Consensus statements have recommended stringent monitoring of metabolic status and cardiovascular risk factors in psychiatric patients receiving antipsychotic medications. The statement recommends baseline screening measures at the initiation of any antipsychotic medication. These measures include weight and height to calculate body mass index (BMI), waist circumference, blood pressure, fasting plasma glucose, fasting lipid profile, and personal and family history of metabolic disorders. By completing this assessment, it can be determined if the patient is overweight (BMI 25.0-29.9) or obese (BMI >30), has prediabetes (fasting plasma glucose 120-125 mg/dL) or diabetes (fasting plasma glucose >126 mg/dL), hypertension (blood pressure >140/90 mmHg), or dyslipidemia. If one or more of these disorders are present, the panel recommends initiation of treatment.

The panel also recommends nutritional and physical-activity counseling for all patients who are overweight or obese, especially if an atypical agent will be initiated. Particular importance is placed on the education of patients, caregivers, and family members on signs and symptoms of diabetes and also on the possible metabolic adverse effects associated with atypical agents.

Baseline screening measures should be followed by ongoing monitoring. Reassessment of all measures, except personal and family history and waist circumference, is recommended after 12 weeks of treatment for all patients treated with atypical antipsychotic medications. Thereafter, fasting plasma glucose, blood pressure, and waist circumference assessments should be completed annually and fasting lipid profile measured every 5 years. Weight should be followed monthly for the first three months and quarterly thereafter. The panel recommends switching to an agent with less deleterious effects on metabolic functions if a patient experiences 5% increase in body weight and/or worsening glycemia or dyslipidemia at any time during therapy. This should be done through cross titration and gradual discontinuation of the current medication. The initial dosage and escalation strategy of the new agent depend on the individual profiles of each medication. Along with altering the treatment, the panel recommends dietary restriction, exercise, and behavior modification.  Small, short-term studies have reported this approach to be successful in managing patients with weight gain.38 Pharmacologic interventions to reduce weight gain have not been found to be dependably effective in patients receiving atypical antipsychotics and should be discouraged.39,40

Atypical antipsychotics are used extensively for FDA-approved indications, including schizophrenia. These agents are considered first-line treatments and have significant advantages over the typical antipsychotics due to their lower risk of extrapyramidal side effects and their beneficial effects on negative symptoms, cognition, and mood. Recent reports on weight gain, new-onset type 2 diabetes, and dyslipidemias require patients to receive ongoing monitoring for these conditions. Although certain atypical antipsychotics, such as olanzapine and clozapine, have been associated with the greatest weight gain and the highest risk of diabetes and dyslipidemia, not all patients taking these agents gain a significant amount of weight. Although there are differences in potential weight gain and, consequently, dyslipidemias among the atypical antipsychotics, differences in risk for diabetes are not as easily quantifiable. This may be due in part to the uncertain etiology of these metabolic abnormalities, but overall their prevalence seems to correlate with weight gain. Risperidone and quetiapine have been shown to have intermediate effects, while ziprasidone and aripiprazole are reported with little or no significant weight gain, diabetes, or dyslipidemia.

The choice of atypical antipsychotic includes many factors, with the risk of developing metabolic disorders an important consideration. Any weight gain must be balanced against the clinical efficacy observed. Appropriate interventions may include switching to another agent if therapeutically feasible, dietary modification, or exercise. Management of comorbid obesity, diabetes, and metabolic syndrome may require joint efforts on the part of primary care physicians, psychiatrists, and pharmacists. The health implications of long-term therapy with atypical antipsychotics are of growing concern and may well be more dangerous than the extrapyramidal symptoms typically associated with the older, typical agents. There is an urgent need for well-designed, randomized, controlled clinical trials to firmly assess both the differential effects of atypical antipsychotics on weight gain and associated metabolic changes. Meanwhile, the well-known benefits shown by some atypical antipsychotics in reducing akathisia and other extrapyramidal adverse effects and improving cognition should be carefully balanced with the problems of weight gain, other metabolic complications, and higher health care costs

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