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CURRENT DRUG THERAPY

MANU MATHEWS, MD DAVID J. MUZINA, MD* CME Department of Psychiatry and Psychology, Vice Chair for Research and Education, CREDIT Cleveland Clinic Director of the Bipolar Disorders Research Unit; and Director of Adult Inpatient Services, Department of Psychiatry and Psychology, Cleveland Clinic

Atypical : New drugs, new challenges

■ ABSTRACT ECOND-GENERATION (“ATYPICAL”) antipsy- S chotic drugs are much less likely than typ- Compared with the first-generation, or “typical” ical antipsychotics to cause movement disorders. drugs, second-generation or atypical But the newer drugs come with a new variety of antipsychotics cause fewer extrapyramidal (motor) side effects—ie, metabolic complications. This problems, but they pose new challenges, as they often presents a treatment challenge, since schizo- contribute to metabolic disturbances such as weight gain, phrenic patients have been found to be predis- hyperlipidemia, insulin resistance, and type 2 diabetes posed to diabetes. mellitus. Patients taking atypical antipsychotics should be In this article we will offer brief profiles of monitored for glycemic and cardiovascular risk factors the atypical antipsychotics commonly used in and should receive treatment for such problems as they the United States, with particular emphasis on the metabolic disturbances that have been arise. attributed to their use. ■ KEY POINTS ■ THE FIRST VS THE SECOND GENERATION The atypical antipsychotics available in the United States are (Clozaril), (Zyprexa), Antipsychotics are among the most widely used drugs in psychiatric practice. They were (Risperdal), (Seroquel), (Geodon), originally intended primarily for the treat- (Abilify), and (Invega). ment of , but over the years their use has spread to other psychotic spectrum dis- Although extrapyramidal effects are much less common orders, bipolar disorder, anxiety and related with atypical antipsychotics, they can sometimes still disorders, posttraumatic stress disorder, deliri- occur, especially if very high doses are used. um, and personality disorders.1

Patients with schizophrenia are predisposed to diabetes. The typical antipsychotics Use of atypical antipsychotics heightens this risk. First-generation antipsychotics, although effective, have been gradually falling out of Of the atypical antipsychotics, clozapine and olanzapine favor because of their side effects, especially cause the most weight gain and pose the highest risk of their extrapyramidal effects, including parkin- sonism, acute dystonic reactions, akathisia, metabolic disturbances. and tardive dyskinesia. The typical antipsychotics are broadly Of the atypical antipsychotics, ziprasidone and classified into two categories: aripiprazole cause the least weight gain. • : (Thora- zine), (Mellaril), (Prolixin), pericyazine (Neuleptil), *Dr. Muzina has disclosed that he has received honoraria from AstraZeneca for consulting, and from AstraZeneca, Pfizer, Eli Lilly, GlaxoSmithKline, the France Foundation, CME Inc, and The Peer (Trilafon), (Stelazine), Group for teaching and speaking. (Piportil)

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TABLE 1 Side effects associated with receptor blockade

RECEPTOR BLOCKED SIDE EFFECT

Alpha 1 adrenergic Orthostatic hypotension, sexual side effects, nasal congestion

Muscarinic M1 Anticholinergic: constipation, blurring of vision, urinary retention Histamine H1 Sedation and weight gain Serotonin 5-HT2 Weight gain, increased appetite D2 Extrapyramidal effects (parkinsonism, dystonia, akathisia, tardive dykinesia), elevated prolactin

• : (Haldol), quetiapine (Seroquel), ziprasidone (Geodon), (Inapsine), bromperidol, and others. aripiprazole (Abilify), and clozapine. Ami- First-generation antipsychotics are as and are not sold in the effective as second-generation drugs in treat- United States. ing the “positive” symptoms of schizophrenia, such as hallucinations, delusions, and para- What is atypical about atypical noia, although they vary in their propensity to antipsychotic drugs? cause side effects.2 The classic definition of “atypical” is a chemi- cal that has clinical antipsychotic effect while The atypical antipsychotics producing minimal catalepsy in animal mod- The high rates of extrapyramidal side effects els.9 The atypicals also: with first-generation antipsychotics, their sub- •Have minimal extrapyramidal side effects or optimal effectiveness against schizophrenia’s movement disorders at antipsychotic doses ‘Atypical’ cognitive symptoms (eg, disorganized thoughts, • Do not or minimally elevate prolactin means fewer poor memory, and difficulty concentrating, fol- • Significantly reduce positive and negative lowing instructions, and completing tasks) and symptoms of schizophrenia.10,11 motor its “negative” symptoms (lack of motivation All antipsychotics block the subtype of problems, little and drive, lack of pleasure from activities, designated D2, which restricted affect), and experience with the first mediates movement. However, the atypical prolactin effect, atypical antipsychotic, clozapine (Clozaril), all antipsychotics have less affinity for this recep- reduction of all contributed to the development of newer tor subtype and dissociate from it faster, and symptoms antipsychotic drugs, broadly classified as atypi- these features may be the key to their “atypi- cal. cality.”12,13 Animal studies have also suggested Some atypicals, such as clozapine, risperi- that if the number of Fos-positive cells in the done (Risperdal), olanzapine (Zyprexa), and core of the nucleus accumbens is greater than amisulpiride, may be superior to first-genera- in the striatum, the drug may be considered tion antipsychotics in alleviating negative atypical.14 Other proposed molecular markers symptoms3–5 and cognitive symptoms.6–8 of atypicality include antipsychotic-induced Second-generation antipsychotics are a depolarization-inactivation of A10 neurons, heterogenous group. Because they act on internalization of 5-HT2A receptors, and neu- many different receptors (eg, dopamine, sero- roplasticity in the striatum.15,16 tonin [5-hydroxy-tryptamine], alpha adrener- ■ gic, histamine H1, and muscarinic M1), their CLOZAPINE: NOW A SECOND-LINE DRUG exact mechanism of action is poorly under- stood. TABLE 1 lists the major side effects associ- Clozapine, a dibenzodiazepine, was the first ated with blockade of five types of receptor. atypical antipsychotic to be marketed in the The most commonly used atypicals in the United States.11 Clozapine is unique for its United States are olanzapine, risperidone, very low incidence of extrapyramidal effects,

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HALF-LIFE STARTING DOSE AVERAGE DOSE AVERAGE DOSE AVERAGE ROUTES OF (HOURS, MEAN) (TOTAL MG/DAY) RANGE MG/DAY RANGE MG/DAY MAINTENANCE ADMINISTRATION (FIRST EPISODE) (RECURRENCE) DOSE (MG/DAY)

Clozapine 10–105 25–50 150–300 400–600 400 Oral (Clozaril) Risperidone 3–24 1–2 2–4 4–6 4–6 Oral, depot (Risperdal) Olanzapine 20–70 5–10 10–20 15–30 10–20 Oral, intramuscular (Zyprexa) Quetiapine 4–10 50–100 300–400 500–800 400–500 Oral (Seroquel) Ziprasidone 4–10 40–80 80–120 120–200 120–160 Oral, intramuscular (Geodon) Aripiprazole 75–96a 10–15 10–30 15–30 15–30 Oral (Abilify)

aThis is the half-life if we take into account its active metabolite REPRINTED FROM PSYCHIATRY SECOND EDITION THERAPEUTICS BY TASMAN, KAY AND LIEBERMANN. PERMISSION TO PRINT GRANTED BY JOHN WILEY & SONS LIMITED. COPYRIGHT JOHN WILEY & SONS LIMITED. REPRODUCED WITH PERMISSION. but it causes agranulocytosis in about 1% of where they are not allowed to smoke, but patients, which has curtailed its widespread have a relapse when they get out and start use.9 Clozapine is also unique in its mechanism smoking again.18,19 Clozapine is a of action, having one of the most widespread Another interaction is the elevation of second-line neuroreceptor affinities among all antipsy- clozapine levels when combined with citalo- chotics with particular selectivity to the recep- pram (Celexa). drug, used tors in the mesolimbic system (A10 region).17 when two other Side effects Indications Clozapine-induced agranulocytosis, as described antipsychotics Clozapine is indicated for schizophrenia but in earlier, has been found to occur in 1% of users. have failed view of its side effects is generally used as a Its affinity for alpha adrenergic receptors is second-line drug, ie, when two other antipsy- responsible for sexual side effects and orthosta- chotics have failed. Clozapine is also the only sis, histamine H1 receptor blockade leads to drug other than lithium (Eskalith and other sedation and weight gain, and muscarinic M1 lithium preparations) that has been shown to receptor blockade leads to anticholinergic side decrease suicides. effects. There have been postmarketing reports Paralytic ileus has also been cited as a of fatal myocarditis. Its use is also related to contraindication for clozapine use. seizures in 2% of patients taking < 300 mg/day, in 3% to 4% taking 600 mg/day, and in 5% tak- Pharmacokinetics: Interactions ing 600 to 900 mg/day. Clozapine is absorbed almost completely after oral ingestion, is 90% protein-bound, and is Monitor the white blood cell count metabolized by the liver. Its notable interac- Due to the risk of agranulocytosis, a baseline tion is with cigarette smoking, which induces white blood cell count and absolute neutrophil its metabolism by the CYP1A2 enzyme of the count and registration with the National cytochrome P450 complex. Many patients get Clozapine Monitoring Registry are mandatory. their symptoms under control in the hospital, The patient should also have weekly tests for

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2 the first 6 months and, if the results are satis- and 5-HT2A receptors, but is more potent at factory, can be monitored every other week the former. A dosage of 10 to 20 mg/day of thereafter for an additional 6 months, and after olanzapine results in 71% to 80% of D2 recep- that once a month. The target blood counts, tor “occupancy,” whereas 30 mg/day results in both before treatment and during the monitor- a greater than 80% occupancy,24 which may ing phase, are a white blood cell count greater explain the higher rate of extrapyramidal than 3,500/mm3 and an absolute neutrophil symptoms at these doses. Olanzapine, like count greater than 2,000/mm.3 clozapine, binds to a broad range of receptors. Dosages of clozapine and the other atypi- cal antipsychotics are shown in TABLE 2. Indications Olanzapine is approved for the treatment of ■ RISPERIDONE: WIDELY USED schizophrenia and acute bipolar mania.

Risperidone, a compound, was Pharmacokinetics the second atypical antipsychotic to be market- Olanzapine is well absorbed orally and has a ed in the United States and is widely used. It half-life of 20 to 70 hours, which allows for has a high affinity for D2 and 5-HT2A receptors. once-a-day dosing. Olanzapine is also avail- able in a short-acting intramuscular injectable Indications form. As with clozapine, smoking induces its Risperidone is indicated for schizophrenia and metabolism and clearance. to treat the manic symptoms of acute manic or mixed episodes associated with bipolar I disor- Side effects der. Risperidone is the only antipsychotic Some of the side effects of olanzapine are indicated for schizophrenia that is available as weight gain, sedation, orthostatic hypoten- a long-acting solution for depot injection. sion, and constipation. It is second only to clozapine in causing weight gain.25 A number Pharmacokinetics of case reports have linked olanzapine and Dose The drug is rapidly absorbed orally and under- clozapine treatment with an increased risk of adjustment goes significant first-pass metabolism. As it is type 2 diabetes mellitus.1,26 Patients on olan- eliminated in part renally, dose adjustment may zapine report significantly lower rates of of risperidone be needed in patients with renal impairment. insomnia, possibly as a result of its sedating may be needed properties.22 Side effects in those with The rates of extrapyramidal side effects are ■ QUETIAPINE renal comparable with those of some of the other sec- impairment ond-generation antipsychotics, but patients Quetiapine, a dibenzothiazepine, has a greater taking doses greater than 6 mg/day may experi- affinity for 5-HT2 receptors than for D2 recep- 20,21 ence significant extrapyramidal side effects. tors. It also has an affinity for H1 and alpha 1 Risperidone has a low propensity to cause anti- and alpha 2 adrenergic receptors.9,27 The low cholinergic side effects. However, in the D2 affinity that it shares with clozapine corre- Clinical Antipsychotic Trials of Intervention sponds to a low incidence of extrapyramidal Effectiveness (CATIE) study, it was the only side effects. one of the antipsychotic drugs studied that was associated with a substantial increase in levels Indications of prolactin.22 Quetiapine is indicated for mania associated with bipolar disorder and for schizophrenia.28,29 ■ OLANZAPINE: ACTION SIMILAR TO CLOZAPINE Pharmacokinetics Quetiapine is one of the most rapidly absorbed A dibenzodiazepine in structure, olanzapine oral antipsychotics. Its absorption is enhanced has a mechanism of action similar to that of when given with food. It is 83% protein-bound 23 18 clozapine. It is antagonistic at both the D2 and has an elimination half-life of 7 hours.

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Downloaded from www.ccjm.org on September 25, 2021. For personal use only. All other uses require permission. Side effects Indications Prominent side effects of quetiapine include Aripiprazole is indicated for the treatment of sedation, tachycardia, and agitation. Due to acute mania and for maintenance therapy of its low affinity for D2 receptors, extrapyrami- bipolar I disorder. In schizophrenia, it is indi- dal effects are rare. cated for the treatment of acute exacerbations of schizophrenia and for maintenance therapy. ■ ZIPRASIDONE Pharmacokinetics Ziprasidone is a benzisothiazolyl Aripiprazole is well absorbed orally and under- derivative. The significant receptor affinities goes extensive hepatic metabolism.1 to be noted include 5-HT1A, which may indi- cate efficacy in anxiety. It has shown benefits Side effects in affective symptoms for patients with schiz- Aripiprazole has been associated with mini- ophrenia,30 possibly due to its serotonergic mal weight gain and metabolic changes. and norepinephrine reuptake blockade. While earlier data may have indicated a very low incidence of extrapyramidal side effects, Indications the rates are similar to those of olanzapine and Ziprasidone is indicated for the treatment of risperidone if akathisia is taken into account. schizophrenia. ■ PALIPERIDONE Pharmakokinetics Ziprasidone has an intermediate rate of Paliperidone (Invega) is the newest atypical absorption, and, as with quetiapine, absorp- antipsychotic to be approved. It is a 9-hydroxy tion is enhanced by food.19 Ziprasidone is also metabolite of risperidone. Its receptor profile available in a short-acting intramuscular is expected to be similar to that of risperidone. injectable form. There are no studies comparing it with other atypical antipsychotics. Side effects Ziprasidone Due to its lack of affinity for H1 and M1 recep- Indications and aripiprazole tors, weight gain, sedation, and anticholiner- Paliperidone is currently licensed for treat- gic side effects are minimal, as shown in the ment of schizophrenia, and trials are under do not appear CATIE study.22 There was no significant pro- way to study its efficacy in the treatment of to contribute longation of the QTc interval in this trial, bipolar disorder. although previous studies had suggested that to diabetes risk ziprasidone prolonged the QTc interval more Pharmacokinetics than any other antipsychotic except sertin- As with risperidone, dose reduction is recom- dole and thioridazine.31 mended in moderate or severe renal impair- Due to the risk of QTc prolongation, ziprasi- ment.33 done use has been contraindicated in patients with QTc prolongation, recent acute myocardial Side effects infarction, and uncompensated heart failure, Trials so far show an increased risk of and in those taking other QTc-prolonging drugs. extrapyramidal side effects compared with Ziprasidone should be avoided or discontinued if placebo. The data at this time are insufficient the QTc is greater than 500 msec. for comment on metabolic risk.

■ ARIPIPRAZOLE ■ ANTIPSYCHOTIC DRUGS AND MOVEMENT DISORDERS Aripiprazole is the newest antipsychotic to be licensed. It is a partial with All antipsychotics have been implicated to 32 a high affinity for D2 and D3 receptors. It some extent in the development of movement induces “functionally selective” activation of disorders. These are primarily of extrapyrami- 32 D2 receptors coupled to diverse G proteins. dal origin and include akathisia, parkinson-

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TABLE 3 chotic treatment is started. Parkinsonism is characterized by rigidity, Metabolic effects bradykinesia, tremors, and shuffling gait. of atypical antipsychotic drugs Dyskinesia. Long-term blockade and up-

DRUG WEIGHT GAIN RISK OF DIABETES WORSENING LIPID regulation of D2 receptors in the nigrostriatal PROFILE pathway can cause tardive dyskinesia, a chron- ic and essentially irreversible movement disor- Clozapine +++ + + der. In long-term studies, first-generation Olanzapine +++ + + antipsychotics have been associated with an incidence of tardive dyskinesia of approxi- Risperidone ++ D D mately 5% per year in adults12,13,37 and 25% to Quetiapine ++ D D 30% in elderly patients.14–16,23 The symptoms include involuntary movements of the tongue a Aripiprazole +/– – – and mouth, irregular involuntary movements Ziprasidonea +/– – – of the extremities, and to-and-fro movement of the spine. + indicates an increase; – indicates no effect; D indicates discrepant results Neuroleptic malignant syndrome is an aNewer drugs with limited long-term data acute and dangerous extrapyramidal side effect COPYRIGHT 2004 AMERICAN DIABETES ASSOCIATION. FROM AMERICAN DIABETES of antipsychotic drugs characterized by a triad ASSOCIATION, AMERICAN PSYCHIATRIC ASSOCIATION, AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS, NORTH AMERICAN ASSOCIATION of rigidity, hyperthermia, and autonomic FOR THE STUDY OF OBESITY. DIABETES CARE 2004; 27:596–601. instability, along with elevated creatine phos- REPRINTED WITH PERMISSION FROM THE AMERICAN DIABETES ASSOCIATION. phokinase levels. It is potentially life-threat- ening, with a death rate approaching 20% in untreated cases. ism, and dystonia. Multiple studies have con- firmed that the atypical antipsychotics carry a ■ CARDIAC EFFECTS much lower risk than typical agents.34 Motor side Prolongation of the QTc interval (> 456 effects to Symptoms of dopamine excess msec) by antipsychotic drugs has always gen- and dopamine deficiency erated significant concern. As described earli- watch for: The nigrostriatal pathway of the extrapyrami- er, the risk is greatest with ziprasidone, sertin- akathisia, acute dal system is critical in the regulation of motor dole, and thioridazine.31 The risk of this pro- movement.35 Excess dopamine in this path- longation is arrhythmia, including torsades de dystonia, way is associated with hyperkinetic movement pointes, although to date this has not been parkinsonism disorders such as chorea, tics, and dyskinesia. reported, either with therapeutic doses or with Deficiency of dopamine in this pathway is overdoses of atypical antipsychotics. associated with extrapyramidal symptoms or with side effects, the three most common ■ METABOLIC SIDE EFFECTS being akathisia, acute dystonia, and parkin- OF ANTIPSYCHOTICS sonism.36 Akathisia is a form of internal restlessness Diabetes and agitation characterized by the inability to Data from most studies suggest that the preva- sit still, by pacing, rocking, and shifting of lence of both diabetes and obesity in people weight while standing, and by tapping of the with schizophrenia and affective disorders is feet. The onset is usually days to weeks after 1.5 to 2.0 times higher than in the general the start of treatment and can be incorrectly population.1 The incidence of impaired glu- diagnosed as anxiety or worsening of anxiety. cose tolerance in first-episode schizophrenic Dystonia, an acute spasm of muscle patients who have not yet taken antipsychot- groups, presents with fixed upper gaze, torti- ic drugs (“drug-naive” schizophrenic patients) collis, and facial muscle spasm resulting in gri- is 15%.38 The prevalence of diabetes in macing, clenched jaw, and difficulty with patients with schizophrenia in the days before speech. This usually occurs soon after antipsy- atypical antipsychotic drugs were widely used

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Downloaded from www.ccjm.org on September 25, 2021. For personal use only. All other uses require permission. ranged from 5.1% to 15%,39 suggesting that fluphenazine, and aripiprazole have the low- these patients are predisposed to diabetes, est risk.26,47,48 independently of treatment with atypical Recent studies show that patients on antipsychotic drugs. Patients on atypical olanzapine gain more weight than patients on antipsychotics have been found to be 9% any other antipsychotic tested, with an aver- more likely to develop diabetes than those age weight gain of 2 lb (0.9 kg) per month. A taking conventional antipsychotics.40 larger proportion of patients in the olanzapine Clozapine and olanzapine have been group than in the other groups gained 7% or associated with a higher risk of diabetes than more of their baseline body weight (30% vs other agents in many studies (TABLE 3).1,26 7% to 16%, P < .001).14 The onset of rapid Other studies have shown these cases to be a weight gain occurs within a few months of combination of new-onset diabetes, exacerba- treatment and fails to plateau 1 year after tion of preexisting diabetes, and presentations treatment.22,26,48,49 of complications such as metabolic acidosis or Hunger and satiety may be altered in peo- ketosis.41,42 No increase in risk was found with ple taking atypical antipsychotics because of risperidone. the known binding affinities of these drugs to In addition to identifying effects of serotonin, norepinephrine, dopamine, and antipsychotic drugs on weight and adiposity, particularly histamine H1 receptors. studies suggest that atypical antipsychotics may have an independent effect on insulin Dyslipidemia sensitivity. Studies by Henderson et al43,44 The development of dyslipidemia appears to comparing insulin sensitivity in patients tak- correlate with weight gain. In a study compar- ing clozapine, olanzapine, or risperidone ing clozapine, olanzapine, haloperidol, and showed a significant difference in insulin sen- risperidone, mean cholesterol levels increased sitivity between the clozapine and risperidone in patients taking clozapine and olanzapine.50 groups and between olanzapine and risperi- No such association was seen in patients on done, with the clozapine and olanzapine ziprasidone in a separate study51 comparing it groups showing lower insulin sensitivity num- with olanzapine, although significant increases Patients on bers than the risperidone groups (higher num- occurred in fasting insulin levels, triglycerides, most atypical bers are better).43,44 A comparison of olanza- and body weight in the olanzapine arm of the pine and aripiprazole in schizophrenic study. In another population-based case-control vs typical patients showed an increase in serum glucose study,52 the chance of developing hyperlipi- antipsychotics in the olanzapine group.45 demia was five times higher in schizophrenic Ziprasidone, in spite of the limited clini- patients taking olanzapine, three times higher are 9% more cal and research data, does not appear to pre- in those taking typical antipsychotics, and no likely to dispose significantly to this risk. In some cases, higher in those taking risperidone.52 develop hyperglycemia resolved promptly after the The study comparing aripiprazole with patient stopped taking the atypical antipsy- olanzapine45 showed no increase in serum diabetes chotic. triglyceride or glucose levels in the aripipra- zole group, although a significant unfavorable Weight gain change in both levels was noted in the olan- A study by Resnick et al46 showed that the zapine group. odds of developing diabetes mellitus increas- In the CATIE study,22 olanzapine had es as the body mass index increases, and that effects consistent with the potential develop- insulin sensitivity decreases as the amount of ment of the metabolic syndrome and was asso- abdominal tissue increases. Resnick et al ciated with greater increases in glycosylated concluded that abdominal fat is the best pre- hemoglobin, total cholesterol, and triglyc- dictor of impaired glucose regulation.46 erides after randomization than were the other Separate meta-analyses have shown that, of study drugs, even after adjustment for dura- the atypical antipsychotic drugs, clozapine tion of treatment. Ziprasidone was the only and olanzapine have the highest propensity study drug associated with improvement in to cause weight gain, and that ziprasidone, each of these metabolic variables.

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TABLE 4 Consensus monitoring recommendations for patients taking atypical antipsychotics

MONITORING FREQUENCYa

Personal/family history Baseline, then annually Weight (body mass index) Baseline; at 4, 8, and 12 weeks; then quarterly Waist circumference Baseline, then annually Blood pressure Baseline; at 12 weeks; then annually Fasting plasma glucose Baseline; at 12 weeks; then annually Fasting lipid profile Baseline; at 12 weeks; then every 5 yearsb

aMore frequent assessments may be warranted based on clinical status. bRecent consensus among experts tends toward annual checks. ADAPTED FROM AMERICAN DIABETES ASSOCIATION, AMERICAN PSYCHIATRIC ASSOCIATION, AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS, NORTH AMERICAN ASSOCIATION FOR THE STUDY OF OBESITY. DIABETES CARE 2004; 27:596–601. REPRINTED WITH PERMISSION FROM THE AMERICAN DIABETES ASSOCIATION.

Based on the above discussion, a list of change in weight after a change in medica- atypical antipsychotic drugs according to their tion. propensity to cause dyslipidemia, from most • The patient’s psychiatric illness should likely to least likely, would be as follows: cloza- not discourage clinicians from addressing the pine, olanzapine, quetiapine, ziprasidone, and metabolic complications for which these aripiprazole.53 patients are at increased risk.1 Monitoring should be performed as shown Patients taking ■ MONITORING FOR GLYCEMIC AND in TABLE 4. It should be determined whether the atypical anti- CARDIOVASCULAR RISK FACTORS patient is: • Overweight (body mass index 25.0–29.9 psychotics The association of obesity, diabetes, and dys- kg/m2) or obese (body mass index ≥ 30) require lipidemia with cardiovascular disease is well • Prediabetic (fasting plasma glucose known. The relationship of second-generation 100–125 mg/dL) or diabetic (fasting plas- screening for antipsychotics to the development of these ma glucose > 126 mg/dL) body mass major cardiovascular risk factors is of great • Hypertensive (blood pressure > 140/90 index and waist interest, and led to a joint conference in mm Hg) November 2003 of the American Diabetes •Dyslipidemic. circumference Association, the American Psychiatric If any of these conditions is identified, the Association, the American Association of patient should receive appropriate treatment Clinical Endocrinologists, and the North and referral.1 A significant weight gain (> 5%), American Association for the Study of dyslipidemia, and worsening glycemia should Obesity. The result was a consensus statement trigger reduction of the dosing of the current regarding antipsychotic drugs and diabetes,1 antipsychotic drug and “cross-tapering” with a which concluded that: safer antipsychotic (ie, starting a safer drug at a •Given the serious health risks, patients low dose and gradually increasing the dose while taking second-generation antipsychotics decreasing the dose of the first drug). should receive appropriate baseline screening The consensus document also includes and ongoing monitoring. recommendations for nutritional and physical •The initial physical screening should activity counseling for all patients who are include the patient’s height and weight (body overweight or obese, particularly if they are mass index) and waist circumference. starting treatment with a second-generation • It is particularly important to monitor any antipsychotic that is associated with signifi-

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Downloaded from www.ccjm.org on September 25, 2021. For personal use only. All other uses require permission. cant weight gain. Referral to a weight man- drugs are at higher risk of death than those agement program may be appropriate.1 who take a placebo. Although the causes of Patients, family members, and all health death are varied, most deaths appear to be care professionals should be aware of the signs either from cardiovascular disease (heart fail- and symptoms of potentially life-threatening ure, sudden death) or from infections (mostly complications, such as diabetic ketoacidosis pneumonia). and nonketotic diabetic acidosis. For patients The US Food and Drug Administration who are at high risk of metabolic complica- has recommended a “black box” label warning tions and who are taking other drugs associat- of this risk for all atypical antipsychotic drugs. ed with weight gain (eg, valproate [Depa- This concern emerged from a clinical trial kote], lithium, medroxyprogesterone [Depo- evaluating risperidone in the management of Provera]), it may be preferable to start treat- behavioral and psychological symptoms of ment with an atypical antipsychotic drug with dementia, and a subsequent meta-analysis of a lower propensity to cause weight gain and the risperidone trials for this indication also glucose intolerance.3 showed more cerebrovascular adverse events In summary, the panel recommends the in participants receiving risperidone (4%) following: than among participants receiving placebo • Consideration of metabolic risks when (2%).54 starting second-generation antipsychotics Pooled data from clinical trials evaluating • Patient, family, and caregiver education olanzapine for the treatment of behavioral • Baseline screening and psychological symptoms of dementia have • Regular monitoring shown that it may also be associated with an •Referral to specialized services when increased risk of adverse cerebrovascular appropriate.1 events.55 These data suggest around a three- fold increase in the relative risk of cerebrovas- ■ WARNING ABOUT USE cular events among people taking risperidone OF ATYPICALS IN DEMENTIA or olanzapine. Some evidence suggests no dif- ference in the risk of stroke between atypical Elderly patients with dementia-related psy- and typical antipsychotics in patients with chosis treated with atypical antipsychotic dementia.56 ■

■ REFERENCES

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