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F E A T U R E A R T I C L E

Diabetes, Psychiatric Disorders, and the Metabolic
Effects of Antipsychotic Medications
Maria D. Llorente, MD, and Victoria Urrutia, MD

sis of diabetes can lead to increased order, either as monotherapy or as

D
iabetes is considered to be one
of the most psychologically levels of anxiety, depressive symptoms, adjuncts to mood stabilizers. Common
demanding of the chronic med- and lowered self-esteem. This is espe- off-label uses of these medications
ical illnesses and is often associated cially true in individuals who have include the treatment of the behavioral
with several psychiatric disorders. underlying psychiatric disorders. and psychological symptoms of demen-
Antipsychotic medications, first intro- Literature has suggested that certain tia (BPSDs), psychotic and treatment-
duced in the 1950s, are a vital compo- psychiatric illnesses may be independ- resistant depressions, autism, behavioral
nent of the medical management of sev- ent risk factors for diabetes. problems associated with developmen-
eral of these psychiatric disorders. These Additionally, poorer glycemic control2 tal disorders, and post-traumatic stress
medications are often prescribed by and resultant increases in diabetes- disorder.
nonpsychiatric physicians. During the related complications3 have been asso- The first-generation (also called
period 1997–2000, according to a large ciated with the presence of a psychi- “conventional” or “typical”) antipsy-
U.S. survey, nearly 1% of all health care atric disorder. Much interest has been chotics (Table 1) are effective in treating
visits resulted in an antipsychotic pre- generated recently because of increas- the so-called positive symptoms of
scription, and almost one-third of these ing reports of a possible causal rela- schizophrenia, most notably hallucina-
prescriptions were written by nonpsychi- tionship between some of the newer tions, delusions, aggression and hostility.
atrists.1 The use of newer “atypical” antipsychotic medications and metabol- Their primary disadvantage has been the
antipsychotics, in particular risperidone ic abnormalities. lack of response of negative symptoms
and olanzapine, increased during this Antipsychotic medications are (such as apathy, social isolation and
period, whereas the use of conventional widely used to treat a variety of psychi- withdrawal, and lack of motivation) and
antipsychotics decreased. atric disorders. They are the foundation the high rate of extrapyramidal side
This article will review the atypical, of treatment for psychotic disorders and effects, including dystonic reactions,
or second-generation, antipsychotics and are primarily indicated to treat acute akathisia, drug-induced Parkinsonism,
their current uses. The relationship exacerbations of schizophrenia and to and tardive dyskinesia.
between diabetes and two of the most prevent relapses. Several of these agents Both the efficacy and adverse
frequent indications for the use of these have also received Food and Drug effects of these drugs are associated
medications (schizophrenia and behav- Administration (FDA) approval to treat with antagonism at the D2 receptors.
ioral and psychological symptoms of manic and mixed phases of bipolar dis- Efficacy is associated with at least 60%
dementia) will be examined. Additional- occupancy of these receptors. However,
ly, this article will explore the complex IN BRIEF when receptor occupancy exceeds 80%,
association between antipsychotic med- there is an increased risk of acute
ications and obesity, hyperglycemia, and Psychiatric disorders can be a risk extrapyramidal symptoms, as well as
dyslipidemias. factor for, as well as a complication hyperprolactinemia.
of, diabetes. Antipsychotic medica- The development of the second-gen-
Indications for Antipsychotic tions, widely used to treat a variety of eration agents (or “atypicals”) came
Medications psychiatric conditions, are also asso- from the need for effective antipsy-
The frequent co-occurrence of diabetes ciated with diabetes. This article chotics that caused fewer and less severe
and psychiatric disorders has been rec- explores the complex relationship side effects. The effectiveness of these
ognized for several centuries and is among psychiatric disorders, antipsy- drugs appears to be comparable to that
thought to be related to several factors. chotic medications, and risk factors of older agents in treating positive symp-
Because patients are responsible for for metabolic syndrome and diabetes. toms of schizophrenia,4 whereas the rela-
95% of disease management, a diagno- tive effect size on negative symptoms

18 Volume 24, Number 1, 2006 • CLINICAL DIABETES

have unfortunate- experience a variety of BPSDs requiring compare atypical antipsychotics. developed in collaboration with the Antipsychotic medications. in particular. will ly the newer atypicals.12 com- pared 26 antipsychotic drug-naive Daily Dose (mg/day) patients with schizophrenia with age- Acute Maintenance Geriatric and sex-matched control subjects and Treatment Therapy Dose found a higher prevalence of impaired Conventional Antipsychotics fasting glucose (15 vs. general population. however. The Clinical Antipsychotic Trials prevalence estimates for diabetes among these drugs are more expensive. and/or clinically significant aggression chotics appears to increase the risk of domized clinical trials or meta-analyses or agitation. the general population. ing from 40 to 60% versus 30% of the increased caregiver burden.5 The risks of extrapyramidal compared the efficacy of typical and er in people with schizophrenia than in side effects are generally lower with the atypical antipsychotics in this popula.20. F E A T U R E A R T I C L E Table 1. with risperidone.01). several researchers found that sons. However. to conventional agents in treating refrac. could be the case. population.18 with overall atypical medications. Results for the atyp. and efficacy was because no study has controlled for all lence estimates rather than on long- small. protocol for Alzheimer’s disease. First.17. use of atypical antipsy. 0%.02) Chlorpromazine 300–1. the relative risk of mortality done and olanzapine. although the literature suggests that this however. P < 0.11 More recent studies have report- Antipsychotic Medications53–55 ed similar findings. quetiap. placebo-controlled. tients with Alzheimer’s disease who general adult population.17. For example.and BMI-matched control Clozapine 200–800 200–800 25–50 subjects. Ryan et. patients Aripiprazole 10–30 10–30 5–10 with schizophrenia are more likely than age-matched control subjects to lead a has been modest and not as great as orig. with minimal glucose intolerance and hyperglycemia associated with schizophrenia is adverse effects at the lower doses used to occurred with increased frequency 1. During the early 20th poor in this population for several rea- tistically significant efficacy for risperi. 36-week study will compare treatment ty in the medicated schizophrenic ated with nursing home placement. no It is unclear whether schizophrenia is an Research on diabetes and schizo- difference among the specific agents independent risk factor for diabetes phrenia has largely focused on preva- studied was found. Perphenazine 30–100 30–60 2–8 Drug-naive schizophrenia patients have Fluphenazine 6–20 6–12 2–4 also been found to have more than three Thiothixene 15–50 15–30 2–6 times as much intra-abdominal fat Haloperidol 6–20 6–12 2–4 (which is correlated with insulin resist- Atypical Antipsychotics ance) as age. but as a group. use of the newer atypical antipsy- double-blind. BPSDs are associ. tion. especial- Many patients with dementia will National Institute of Mental Health. century.15 and have other car- ine.000 300–600 25–75 and higher insulin resistance (P < 0.10.21 In addi- A recent literature review6 examined experience delusions or hallucinations tion. a trial 16 to 25%. Daily Dosing Recommendations for Conventional and Atypical cox. It is likely.19 cant metabolic effects.17. symptoms.8 and tobacco use. of Intervention Effectiveness (CATIE) patients with schizophrenia ranging from eral have been associated with signifi. that diabetes outcomes are ical antipsychotics showed modest.13 Risperidone 4–10 4–10 1–2 It is clear. and ine.9 To date. sta.23. ran. This ly contributed to the prevalence of obesi- medication treatment. adverse side effects.22 even. found the prevalence of both diabetes ated with reduced risk of suicide domized clinical trials have directly and obesity to be two to four times high- attempts. acquiring or exacerbating type 2 dia- of antipsychotic drug therapy for patients betes. 2006 19 . causing diabetic with dementia and neuropsychiatric Diabetes and Schizophrenia ketoacidosis and death. olanzapine. no ran. al. citalopram. sedentary lifestyle.24 with the leading CLINICAL DIABETES • Volume 24. with current estimates rang- accelerated cognitive decline. risk for cerebrovascular events7. Number 1. among patients with dementia prae. with frequent occurrence of the major risk factors for diabetes. consume fewer fruits inally hoped. that the preva- Olanzapine 10–20 10–20 5–10 lence of diabetes and its risk factors is Quetiapine 200–800 200–800 50–200 much greater among patients with seri- Ziprasidone 80–160 80–160 — ous mental illness. For typical antipsychotics. chotics in this population is complicated and vegetables.6–2. higher mortality rates. which has been found to be superior by recent reports of a possible increased diovascular risk factors.6 times higher than that of the treat elderly patients with dementia. rarely. and placebo for outpa.5 The exception is clozap.16 Additional studies have tory schizophrenia and has been associ. term diabetes outcomes.14. and sev.

patients with schizo. Number 1. Ziprasi- idea that part of the pathosphysiology of tion tests.38 This weight gain is not The prevalence of type 2 diabetes these deficits and. reaching a maximum gain of high as 75%) of smoking.25 The average age of death is 61 the risk of late-life dementia in a dose. gain. weight. Among the atypical antipsy- end product (AGE) formation. Hummer et al. for up to 1 year.35 weight. Obesity have been implicated. Neuropsy. Antipsychotic Medications and but several neurotransmitter systems tribute to tau protein and tangle forma. clinicians been shown to continue for 30 weeks. type 2 diabetes has been promazine.23 Second. The relationship appears the higher-potency drugs (fluphenazine ical data. presence of obesity in middle age and Clock Drawing Test. an annual basis. has also been associated with and increased levels of stress. is associated with a twofold increased gained > 10% of their initial body tion. AGEs nutritional deficiencies.15 Third. rapid plasma reagin. provides sufficient Weight gain is reported to be lower than diabetes in later life. lems merit a cognitive assessment.34 and type 2 diabetes patients treated with clozapine had versus 76 years for the general popula. Affinity for histamine receptors dementia. The most widely used instrument Weight gain for risperidone and que- studies have found that the risk for is the Mini-Mental State Exam. weight gain. monitor the course of impair. sensitivity and specificity to be used on that seen with olanzapine and clozapine ies. factors at midlife substantially increases been reported. all of Older adults who report memory prob. aripiprazole after 1 year of treatment accelerated rate of advanced glycation nitive impairment. Average weight gain associated with hyperglycemia is accompanied by an Any identified reversible causes of cog. the relative tendency to cause have been demonstrated to accumulate turbances. stops ine-induced weight gain does not appear estimated to be ~ 50%. A laboratory dementia work-up tional drugs. affinity for histaminic receptors. 36% of years for people with schizophrenia dependent manner. thyroid func. that after 1 year of treatment. Olanzapine. should be treated. ziprasidone and arip- diabetes and APOE-4 compared with mulations of the same drug. olanzapine has led A cognitive screening instrument to nearly twice the weight gain of Diabetes and Dementia allows providers to objectively document risperidone. speculation that histamine receptor Further. done is associated with little weight Alzheimer’s disease may be related to els) should also be completed to rule out gain. non. which can worsen medical outcomes. Additionally. a cognitive disorder may be present. insight. neuronal insulin resistance. chotics.40 AGEs also appear to accelerate -amy. even after 1 year of treatment. with risperidone and quetiapine does Alzheimer’s disease.17–29 In animal stud. Conversely. trations. with repeat adminis. associated with lower risks of those without these two factors. or inconsistently to plateau early in treatment. double-blind studies. with the highest to be synergistic. must have a high index of suspicion that Olanzapine.36 but greater than that seen with conven- tors has been found to mimic some fea.31 etiology of cognitive impairment is > ziprasidone = aripiprazole.32 Shortly after the introduction of chlor. Conventional antipsy. with a similar chemical lower levels of psychosocial support.39 lence of dementia. Clozap- adherence to treatment is common and to forget or miss appointments. Initially. of extracellular proteins and may con. appear to correlate with dose. When an older patient begins 30% of their initial body weight. which. poor access to medical care. such as medications. The mechanism of antipsychotics- loid aggregation through cross-linking induced weight gain is undetermined. 20 Volume 24. significant weight gain. It ventional antipsychotic-induced weight for Alzheimer’s disease and vascular was further noted that lower-potency gain. is also fivefold increase in the risk for chotics-associated weight gain appears associated with high rates of weight Alzheimer’s disease for subjects with to be comparable for oral and depot for. Seven patients continued to gain phrenia have high prevalence rates (as Memory deficits are not part of nor. Several prospective ments.37 reported ease. risk of vascular dementia. as does the preva. mal aging. uncertain. iprazole.30 This supports the file. Weight gain associated tures of the neurodegeneration seen in (complete blood count. apparently related to dose and can persist increases with age. 2006 • CLINICAL DIABETES .33 The Among the atypical medications. weight gain is as follows: clozapine in the neuritic plaques and neurofibril.33–35 The effect of diabetes is agents (chlorpromazine and thiori. was ~ 2 kg. have lower affinities for his- presence of multiple cardiovascular risk varying degrees of weight gain have tamine receptors. tiapine appears to be intermediate developing dementia increases with the when used in combination with the among the antipsychotic medications. In prospective. clinicians noticed that blockage was responsible for the con- found to be an independent risk factor antipsychotics use led to weight gain. metabolic pro. structure. F E A T U R E A R T I C L E cause of death being cardiovascular dis. or metabolic dis. chological testing is also helpful if the > olanzapine > risperidone = quetiapine lary tangles of Alzheimer’s disease. depletion of neuronal insulin recep. this checking fingersticks. treatable causes of cognitive impairment. leading to a more than and haloperidol). there was tion and oxidative stress.26 Finally. and it has group often suffers from impaired takes or refills prescriptions. and B12 and folate serum lev. does correlate with medication-induced especially pronounced in carriers of the dazine) induced greater weight gain than weight gain41 and is supported by empir- APOE-4 gene.

com. potency drugs. Koro et al. develop diabetes. ziprasidone. asso. This hyperglycemia antagonists) inhibited cholinergics. ings for both risperidone and quetiap- analyses suggest that conventional and Recently. These drugs may disrupt serum triglyceride levels. directly with weight gain. including small numbers of patients among the various atypical antipsy. pared with 21% of those receiving con. Results of data. Risperidone had 1. was discontinued. return to baseline levels. In 2003. increased appetite and obesity in mice. 2006 21 . Johnson et al. However. This is consistent with early triglyceride levels associated with previ- obesity. Findings are choice for BPSDs. This is likely to explain some serum levels through hypothalamic tiapine.46 found that ine. the geriatric population. Koro et al. Additionally. in the various CLINICAL DIABETES • Volume 24.8 terol. explain some of the inconsistent find- Case reports and retrospective database ance is a possible mechanism. hyperglycemia-related deaths. This may Hyperglycemia patients. A family history for diabetes is findings of a higher association between ous antipsychotic treatment. base analyses. Because several of atypical antipsychotics in older adults of conventional drugs and 2. their lipid levels may have decreased can result in new-onset type 2 diabetes. Most done and ziprasidone had no such Very preliminary data suggest that cases of new-onset type 2 diabetes occur effects.. erides are all associated with obesity FDA issued warnings that the use of ment. and clini. ulation retrospective studies have found would expect that hyperlipidemia Table 2 details the incidence rates of that olanzapine and clozapine are associ. For and are often. Methodologi- ziprasidone’s norepinephrine reuptake hypothalamic regulation of glucose cal problems exist in the results for que- inhibition. studies ventional medicines45 and 71% of a did not control for earlier treatments Antipsychotic Medications and small sample of olanzapine-treated with lipid-lowering drugs. associated with diabetes are also those Divergent results are seen with Most atypicals are antagonists at this that induce the greatest amount of risperidone and quetiapine. vated insulin levels have been found in studied. one increased risk of cerebrovascular events. Behavioral antipsychotic treatment use than in a increased serum triglyceride levels. most of which have antagonistic 46% of clozapine-treated patients. in the associated with risperidone. The low.42 receptor. such as must be sought. the specific second-generation antipsy.42 Several large pop. The doses of quetiapine used chotics. would be missed. regulation have been proposed to explain equivocal regarding changes in choles- HT2C has been associated with this association. are much chotics with respect to the incidence more anticholinergic than high-potency Diabetes and Antipsychotic rates of diabetes. should also be associated with the use these events in pooled samples com- ated with a significantly higher rate of of these medications. and this may partially explain weight gain. however. Additionally. and other nonpharmacological interven- general patient population sample. Number 1. There are patients who found no increase in hyperlipidemia patient reports of increased appetite. were small. Dyslipidemias None of the available antipsychotic Olanzapine had 4.6 times the risk and weight gain.42 in a large medications.22. The cal trials indicate that clozapine and patients and caregivers need to be risk of diabetes. so that a dose-related effect properties at the 5-HT2C receptor. although not always. dents occurred with low frequency. with significant weight gain.44 This hypertriglyceridemia correlates tions should be the first-line treatment of Several mechanisms of glucose dys. found the risk of diabetes associated Antipsychotic Medications and Older adults with antipsychotics to be quite variable. induced insulin secretion by blocking because the primary responsible agent metabolic acidosis or ketosis. the times the risk associated with no treat. cose concentrations. The medications most terol levels. and clozapine (both potent muscarinic were then switched to a different agent. Increased serum levels of total choles. These effects. Although these inci- diabetes than the conventional antipsy. ele. chotics risperidone and quetiapine. and even muscarinic M3 receptor activity. LDL cholesterol. drugs is specifically indicated for use in ated with conventional agents and 5. and triglyc. so other causes smaller studies have reported increased by other receptor activities. is higher with olanzapine use is associated with informed of the association. however. a contributing factor for development of patients who have elevated cholesterol or ciated with significant weight gain or diabetes. Medications population-based. F E A T U R E A R T I C L E Blockade of the serotonin receptor 5. of the variability in weight findings dopamine antagonism. however. in general. suggesting that insulin resist. If patients who had previously tak- atypical antipsychotics are associated in vitro low concentrations of olanzapine en a drug that increases lipid levels with significant increases in fasting glu. pared to placebo. In fact. These findings suggest an added ziprasidone and aripiprazole may not within the first 6 months of treatment role for potent anticholinergic activity as have adverse effects on lipid levels. chart reviews. switching to also associated with an increased risk.2 times the risk associ.2 times the the newer antipsychotics are associated with dementia was associated with an risk of no treatment. case-control study. low-potency conventional antipsychotics either of these medications may lead to a There seems to be variability among and increased weight gain.43. and aripiprazole. can be mitigated absence of weight gain. Risperi.

American Psychiatric ry reported an increased risk of all. rechecked at 12 weeks and annually with no treatment. Haloperidol 329 0. weight. exercise groups are being incorporat- their nursing home. A 2004 consensus to nonpharmacological treatments. An added consideration is that. and lipid levels should be times. Side effect mended dietary restrictions because they mote healthy lifestyle choices. attempts to help with diabetes regimens Treatment Considerations ent. For patients 22 Volume 24. with schizophrenia may have diabetes. may be viewed as intrusive and overpro. F E A T U R E A R T I C L E Table 2.9 1. Medical management. gain in children and adolescents. patients’ weight should be weighed against potential risks. adolescence as a time when the person monitored at each visit. and dyslipidemias. At present. and themselves. It is unknown how much of apine. at must emotionally separate from parental glucose. Diabetes antipsychotics. evaluations at the initiation of medica- four atypical agents (risperidone. mostly institutionalized weight ranged from 5 kg to 21 kg. should be opti. aripiprazole has been studied in a small tional diabetes in female patients. Inquiries should of placebo. The influence of psychological fac. risperidone. there may be risks associated figures in order to affirm a separate iden. and hypertension and be Thus. with an early age of onset. This mized to reduce this risk. disorder). as well as simultaneously adminis. wellness classes for patients and their They are occasionally capable of injur.7 times that ine. elevated lipids. Number 1. however. chotics are not adequately screened for suggests that many BPSDs do respond diabetes risk factors. including those Association. and umbilical the population being studied. American Association of cause mortality in older adults with gain.9 Identification of Risk Factors for randomized clinical trials of atypical including control of glucose. olan. for ly.9 accustomed to frequently communicat- Aripiprazole 938 1. this evaluation should be per- n Drug (%) Placebo (%) formed by a child psychiatrist or psy- Risperidone 1.3 1. who begin to exhibit behavioral or signif. Children Schizophrenia is a devastating illness. risk fac. dia- The mortality rate for elderly patients been associated with the use of clozap. Diabetes control often deteriorates dur. their caregivers and example. Erikson describes Ideally. there are levels should be checked. and. lar events. nutrition and BPSDs can be and often are aggressive. tors for vascular disease should be support group can be beneficial. A tion and how much is simply inherent in sample (n = 14) of children and adoles. Children and adolescents conference of the American Diabetes In 2005. an additional FDA adviso. For example. have a greater effect on weight Clinical Endocrinologists. Antipsychotic medications are the basis tered medications. including history of stroke. while at the same time striving for thereafter. autism. These findings are loss was 3  6 kg). Ideally. ed into mental health programs to pro- relatives. Among American Association for the Study of chotics. significant weight gain has sonal and family history of obesity. ment with these medications must be cents. betes. Parental other medical diseases that may be pres. cardiovascular disease. may fail to adhere to recom. acceptance and belonging from peers. tective. and North dementia treated with atypical antipsy. cents with bipolar disorder.9 The FDA analyzed 17 placebo. the benefits of instituting treat. and queti. hypertension. dyslipidemia. Diabetic teenagers. aripiprazole. quality of care because many patients have other risk factors for cerebrovascu.51 Change in circumference should be measured and jects were frail. increasing- ing other residents or staff members of ing this stage. and quetiapine). In addition. Often. children and adolescents treated for a Obesity40 recommended several baseline controlled randomized clinical trials of variety of conditions (schizophrenia. and lipid vascular disease. Pooled Incidence Rates of Cerebrovascular Events in Randomized icant academic difficulties.4 with chronically ill children and who is Quetiapine 568 0. that are less likely to induce weight Association.47–50 Weight gain associated with also be made regarding history of gesta- the risk is associated with the medica. and with dementia was ~ 1. who are likely to age group. hyperten. unaware of it. These recom- therefore particularly concerning for insufficient data on ziprasidone in this mendations provide for a very high older diabetic patients. and pervasive developmental tion use. ing with diabetic children and adoles.230 4 2 chologist who has experience in working Olanzapine 1. BMI calculated. Baseline blood pres- elderly with multiple risk factors for with 86% losing weight (average weight sure.6 ing with other medical professionals. Blood pressure. families can be helpful. olanzapine. Study sub.6–1. evaluated. fasting plasma glucose. Clinicians should obtain a per- zapine. may Clinical Trials: Antipsychotic Treatment Arm Versus Placebo benefit from a mental health evaluation. Atypical antipsychotics. profiles must be considered in light of want to fit in with peers. baseline height. the placebo response sion.3 0.3 0. tors must also be considered when work. referral to a diabetic teen of treatment for schizophrenia.852 1. 2006 • CLINICAL DIABETES . Many patients taking atypical antipsy- rates have ranged from 36 to 60%. Minimally. Older adults with tity.

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