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 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, and even in bipolar disorder, 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
Antipsychotics and Adverse Effects
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
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
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 bipolar 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). The FDA has approved olanzapine as maintenance treatment of bipolar
disorder and, in a combination pill with fluoxetine, for treatment of patients
with depressive episodes associated with bipolar disorder.
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
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 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
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
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
and Treatment of Metabolic Adverse Events
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.
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
antipsychotics are used extensively for FDA-approved indications including
schizophrenia and, more recently, bipolar mania. 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,
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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