Schizophr Bull 1997 Hansen 567 82

Neuroleptic Intolerance
by Thomas E. Hansen, Daniel E. Casey, and William F. Hoffman
This article reviews antipsychotic medication side

effects, especially those that require the physician to
discontinue or the patient to be noncompliant with
otherwise useful medication. They include such common problems as extrapyramidal syndromes (dystonia, akathisia, drug-induced Parkinsonism, tardive
dyskinesia), sedation, weight gain, and sexual dysfunction, as well as less frequent concerns, such as seizures,
neuroleptic malignant syndrome, agranulocytosis, torsade de pointes, hepatitis, and dermatological and
ophtbalmological syndromes. The adverse events associated with some of the new antipsychotic drugs are
included. Available information about individual susceptibility to side effects is addressed by syndrome.
Schizophrenia Bulletin, 23(4):567-582,1997.
Antipsychotic medications provide the promise of relief
from psychotic symptoms for many patients.
Unfortunately, some patients do not tolerate these potentially life-restoring medications. This neuroleptic intolerance is a function of expected antipsychotic medication
side effects, as well as individual patient vulnerability to
side effects. The ultimate expression of neuroleptic intolerance is noncompliance with antipsychotic medication
and thus failure to improve. More recently developed
medications present the potential for fewer adverse effects
and less neuroleptic intolerance. An understanding of
antipsychotic side effects will help predict the areas in
which this potential is likely to be achieved and those in
which it may not.
The term "neuroleptic" refers to the concept that these
medications "grip" or "take control of the neuron" (Casey
1995), as evidenced by their extrapyramidal side effects
(EPS). Initially, EPS were thought to be required for therapeutic effect. Newer antipsychotic agents demonstrate the
fallacy of this belief (Kane and Freeman 1994); they are
Reprint requests should be sent to Dr. T.E. Hansen, Portland VA

Medical Or., 116A-P, P.O. Box 1034, Portland, OR 97207.
567
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effective in treating psychosis while causing low rates of

EPS. However, the side-effect profile of most medications
includes other neurological and nonneurological symptoms. For the typical antipsychotic, these symptoms can
heuristically be placed along a continuum of potency:
higher potency drags are effective at lower milligram
dosages and are associated with higher rates of EPS but
less sedation, hypotension, and anticholinergic effects;
lower potency drugs behave in an opposite fashion, with
more sedation, hypotension, and anticholinergic effects but
less EPS at a given dosage (table 1). The newer antipsychotic medications do not fall neatly into this pattern.
Most side effects can be understood in terms of their
effects on central neurotransmission or receptor interactions
outside the central nervous system (CNS). For example,
both antipsychotic action and acute EPS have been attributed to dopamine receptor blockade (i.e., interference with
dopaminergic neurotransmission) in various brain areas.
Anticholinergic side effectsdry mouth, blurred vision,
constipation, confusion, temperature dysregulationreflect
activity at central and peripheral muscarinic receptors.
Sedation may be a consequence of antihistaminic, central
anti-alpha-adrenergic, or anticholinergic activities (Bristow
and Hirsch 1993). Although newer antipsychotic medications cause fewer EPS, their activity in a variety of neurotransmitter systems may generate neuroleptic intolerance
for reasons other than EPS.
Many articles have reviewed the undesired effects of
antipsychotic medications (Bristow and Hirsch 1993;
Malhotra et al. 1993; Zaleon and Guthrie 1994; Casey
1995; Goff and Shader 1995; Whitworth and Fleischhacker 1995). In this article we bring together the differing emphases of these reviews, identifying the side effects
that often require medication discontinuation or that contribute to patient noncompliance. We also comment on the
Abstract
Schizophrenia Bulletin, Vol. 23, No. 4, 1997
T.E. Hanscn ct al.
Table 1. Side-effect profile of typical

antlpsychotlc medications
Low-potency
medications
Dosage for antipsychotic efficacy
Incidence of EPS
High (250 to
1,000 mg/day)
Low
Sedation
Hypotension
Anticholinergic effects
High
High
High
High-potency
medications
Low (1 to 20
mg/day)
Moderate to
high
Low
Low
Low
Fortunately, acute dystonic reactions respond rapidly

to anticholinergic medications (e.g., benztropine), and prophylaxis is effective in patients at high risk (Keepers et al.
1983; Keepers and Casey 1986; Arana et al. 1988). With
traditional antipsychotic medications, lower dosage and
the prophylactic use of anticholinergic drugs should reduce
the impact that acute dystonia has on neuroleptic intolerance. Clozapine and the newest antipsychotic medications,
olanzapine and sertindole (Beasley et al. 1996a, 1996fc;
van Kammen et al. 1996), do not seem to cause dystonia.
Drug-induced Parkinsonism (DIP). Like dystonia, DIP occurs during the initial period of antipsychotic
medication exposure (Casey 1991, 1995; Hansen and
Hoffman 1997). No clear symptomatic distinction can be
made between idiopathic Parkinsonism and DIP. The classic triad of bradykinesia, rigidity, and resting tremor, as
well as associated signs of stooped posture, gait disturbance, salivation, and skin changes (seborrheic dermatitis)
occur in both syndromes. Incidence and prevalence rates
of DIP vary with the type of medication, patient factors,
and diagnostic threshold (Hansen et al. 1988; Hansen and
Hoffman 1997), ranging from less than 15 percent to over
50 percent. The gradual onset of symptoms and the
absence of pain contribute to patients feeling less distressed by this symptom than by dystonia and akathisia.
However, its high prevalence and potential consequences
(such as falling) make this syndrome problematic for the
physician considering neuroleptic intolerance. The possibility that acute EPS, especially DIP, is a risk factor for
tardive dyskinesia (TD) adds to this concern (Andrew
1994). Whether the increased risk of TD in patients who
have had acute EPS (Kane et al. 19886) requires the
actual occurrence of the acute EPS or is simply a consequence of a shared underlying pathophysiology (i.e.,
dopamine receptor blockade) is unclear. Still, much of the
effort to develop antipsychotic medications that are not
Note.EPS - extrapyramidaJ side etfects.
Neurological Side Effects

The neurological side effects of antipsychotic medications
include those commonly attributed to the extrapyramidal
system (i.e., EPS); neuroleptic malignant syndrome
(NMS), which may be a variant of acute EPS; seizures;
and cognitive effects including sedation. EPS occur in
most patients prescribed traditional antipsychotic medications and can be bothersome and debilitating to patients,
as well as worrisome to care providers. Though rare in its
fulminant form, NMS generates concern because of its
potential for morbidity and mortality. The risk of seizures
in NMS may cause some physicians to unreasonably limit
use of antipsychotic medications for some patients and
must be monitored when using clozapine. Both sedation
and other cognitive effects can be a source of distress to
patients.
EPS.
Acute dystonia. This side effect occurs early in the
course of treatment with antipsychotic medications or
shortly after dosage is increased (Rupniak et al. 1986;
Casey 1991, 1995). Involuntary contraction or spasm of
various muscle groups can result in painful sustained postures. During contraction, the affected body part may
appear to move in a moderately slow, writhing fashion.
The sustained contraction may transiently relax, only to
be followed by the same writhing movement. The symptoms seen with dystonic reactions include oculogyric
crises, torticollis or opisthotonos, tongue thickening or
protrusion, locked jaw, hand or arm cramps, and laryngeal
568
spasm. Other problems can develop secondary to dystonic

reactions; for example, temporomandibular joint dislocation (Ibrahim and Brooks 1996) and potentially fatal
laryngeal spasm. Dystonic reactions appear more commonly in young male patients receiving potent antipsychotic medications (Keepers and Casey 1986, 1987), but
can occur in lower risk patients or with medications less
likely to cause dystonia, such as risperidone (Faulk et al.
1996). The etiology of acute dystonia seems to be more
complex than simple dopamine receptor blockade: dystonic reactions occur with medications that block
dopamine receptors, but during time periods when drug
blood levels are likely to be falling (Rupniak et al. 1986;
Casey 1991, 1995). The pain, surprise, and bizarre quality
of this side effect may cause patients to refuse antipsychotic medications.
patient factors that interact with drug characteristics to

influence the expression of side effects and the consequence of these factors on compliance and patient dissatisfaction.
Ncuroleptic Intolerance
Akathisia occurs early in the course of antipsychotic

treatment, is associated with higher doses of medication,
and may coexist with other EPS (Sachdev and Kruk
1994). Some investigators report that higher potency
antipsychotic medications are associated more frequently
with akathisia, although this factor was not significant in
logistical regression analysis in the most thorough study
of akathisia conducted to date (Sachdev and Kruk 1994).
Interestingly, despite the low incidence of other acute EPS
with clozapine, akathisia has been reported to occur anywhere from 3 to 39 percent of patients treated with this
low-potency medication (Cohen et al. 1991; Sachdev
1995a).
The best treatment for akathisia is reduction of
antipsychotic dosage or use of beta-adrenergic blocking
agents (Adler et al. 1989; Casey 1991, 1995; Sachdev
19956). Clozapine, despite causing some acute akathisia,
may be an effective treatment for cases of tardive
akathisia (Sachdev 1995a, 19956). The newest antipsychotic medications, olanzapine and sertindole (Beasley et
al. 1996a, 19966; van Kammen et al. 1996), do not seem
to cause acute akathisia at rates that are different from
placebo. Therefore, these medicines may be the treatment
of choice for patients who cannot tolerate akathisia associated with traditional antipsychotic medications.
Much emphasis is placed on the role of medication in
causing EPS, with low-potency and more recent antipsychotics causing an overall lower incidence. Although
associating new antipsychotic medications with lower
degrees of neuroleptic intolerance is warranted, clinicians
should remember that patient characteristics also influence EPS incidence. The role that age and gender play in
increasing the risk of dystonia (with young males at
increased risk) illustrates this concept. Older patients
experience higher rates of DIP (Hansen et al. 1988;
Hansen and Hoffman 1997), whereas younger patients
may have an increased risk of akathisia, at least the
chronic type (Halstead et al. 1994). Women may be at
greater risk for DIP (Hansen and Hoffman 1997) and
chronic akathisia (Halstead et al. 1994). Ethnic background may influence the occurrence of EPS as well
(Sellwood and Tarrier 1994). Asian patients reportedly
require lower doses of antipsychotic medications to
achieve efficacy, with higher haloperidol blood levels at a
given dose (Lin and Finder 1983; Potkin et al. 1994). A
third study did not replicate the latter finding, however
(Sramek et al. 1986). Similar concerns related to AfricanAmericans have been raised (McLeod-Bryant 1992).
Finally, such CNS disorders as human immunodeficiency
virus (HIV) infection may also place a patient at greater
risk of EPS (Swenson et al. 1989; Hriso et al. 1991; Ayuso
1994).
569
neuroleptics (i.e., cause acute EPS) is targeted at reducing

the incidence of DIP (thereby decreasing acute morbidity)
and the eventual risk of TD.
When possible, the primary treatment approach for
DIP associated with traditional antipsychotic medications
is prevention by the use of low dosages. If using a low
dosage is not possible, then substitution of a lower
potency antipsychotic drug or the concomitant use of anticholinergic medications (i.e., benztropine) or the weak
dopamine agonist amantadine is usually needed (Casey
1991, 1995). More potent anti-Parkinsonian agents, such
as L-dopa or bromocriptine, carry with them a greater risk
of exacerbating psychosis or undermining antipsychotic
action through dopamine agonism. Alternatively, DIP may
be reduced or avoided by the use of newer medications.
Although risperidone does cause dose-related DIP at
doses below 8 mg per day, it usually causes less DIP than
is seen with haloperidol in comparable doses (Marder and
Meibach 1994; Casey and Hansen 1995). Clozapine, olanzapine, and sertindole seem to cause DIP at rates that are
not significantly different from placebo (Meltzer 1995;
Beasley et al. 1996a, 19966; van Kammen et al. 1996).
Akathisia. When defined in broad terms, akathisia
probably constitutes the most intolerable acute EPS.
Though originally conceptualized as a subjective sense of
inner restlessness, akathisia also causes characteristic
movements (Barnes 1987; Adler et al. 1989; Halstead et
al. 1994; Sachdev 1994; Casey 1995). Two investigations
(Barnes and Braude 1985; Sachdev and Kruk 1994) came
to similar conclusions about the relative frequency and
types of akathistic movements, with fidgety motion of the
legs when sitting and inability to stand in one place (rocking from foot to foot) being most common. Patients with
motor signs but no subjective complaints may be said to
have pseudoakathisia (Barnes and Braude 1985). Other
researchers require subjective feelings of restlessness that
are especially attributable to the legs, along with motor
signs, to diagnose definite akathisia (Sachdev and Kruk
1994), preferring the term "probable akathisia" for motor
signs without subjective complaints (Sachdev 1994). The
broadest use of the term akathisia applies to patients who
have any complaint of subjective distress while on
antipsychotic medication (Van Putten 1975). Not surprisingly, this broad range of diagnostic standards leads to an
equally wide incidence range (13% to 75%; Ayd 1961;
Van Putten 1975; Adler et al. 1989; Halstead et al. 1994;
Sachdev and Kruk 1994), with 20 percent frequency considered typical (Adler et al. 1989). Regardless of whether
neuroleptic dysphoria is considered a sufficient condition
to define akathisia, dysphoria occurs commonly in
patients with akathisia (Barnes 1987; Halstead et al. 1994)
and undoubtedly contributes to neuroleptic intolerance.
T.E. Hansen et al.
cians are advised to target the most problematic symptoms and carefully monitor the outcome.
Prevention of TD, tardive dystonia, and tardive
akathisia is obviously a goal for development of new
medications. The minimal occurrence of acute EPS in
patients taking clozapine, sertindole, and olanzapine
bodes well for a lower occurrence of TD.
NMS. Much attention has been focused on NMS in the
last 15 years, with multiple studies and reviews
(Levenson 1985; Levinson and Simpson 1986; Pearlman
1986; Pope et al. 1986, 1991; Shalev and Munitz 1986;
Addonizio et al. 1987; Kellam 1987; Lazarus et al. 1989;
Rosebush and Stewart 1989; Kornhuber and Weller 1994;
Keck et al. 1995). Signs and symptoms include dystonia
and Parkinsonism (especially rigidity), fever, autonomic
instability, delirium, myoglobinuria, and elevation of
serum creatinine kinase levels, white count, and liver
function test results. Controversy exists about exactly how
many and which symptoms must be present to make the
NMS diagnosis. Incidence estimates range from 0.02 percent to 3.23 percent (Lazarus et al. 1989), with increased
risk in agitated male patients who have received intramuscular injections of antipsychotic medications in high and
rapidly escalating doses (Keck et al. 1995).
The complex characteristics of NMS confound simple pathophysiological explanations. Dopamine blockade
in the basal ganglia and hypothalamus could cause NMS
(Kornhuber and Weller 1994; Keck et al. 1995). One
group has speculated that the symptoms of NMS can simply be accounted for by acute EPS from dopamine blockade, with a comorbid condition causing the fever symptom (Levinson and Simpson 1986). In addition,
antipsychotic medications with a wide range of potency in
blocking dopamine receptors, including clozapine, can
cause NMS (Shalev and Munitz 1986; Tsai et al. 1995),
which suggests that some alternative or additional drug
mechanisms or patient factors might be operative. Since
affective disorders have been overrepresented in several
case series (Pearlman 1986; Rosebush and Stewart 1989),
a psychiatric disorder may act in concert with drug action
to cause NMS. For example, a condition like mania might
cause dehydration and exhaustion that act as substrates for
NMS. The fact that patients can be rechallenged with
antipsychotic medications and not have a recurrence of
NMS (Rosebush and Stewart 1989; Pope et al. 1991)
requires the contribution to pathophysiology from within
the patient to be potentially transient Comorbid medical
conditions, dehydration, and agitation could fit this
description. NMS would then be dependent on the
patient's health and not be merely a function of a specific
drug.
The risk of TD may influence some clinicians to

avoid the use of antipsychotic medications. Their concerns about legal liability can therefore establish neuroleptic intolerance, even if the patient is unaware of the
symptoms. In cases where TD is severe, clinicians may
choose to use clozapine, with the expectation that at least
the patient will not experience cumulative risk from continued exposure and may benefit from a direct antidyskinetic effect (Tamminga et al. 1994; Meltzer 1995).
Of interest is the finding by several groups of investigators that spontaneous choreoathetoid movements similar to TD occur at substantial rates in schizophrenia
patients who were never treated with neuroleptics (Owens
et al. 1982; Waddington and Youssef 1990; Fenton et al.
1994; Hoffman et al. 1996). These studies suggest that not
all dyskinesia found in schizophrenia patients is due to
neuroleptic treatment. A proportion of the prevalence may
derive directly from the cerebral pathology of schizophrenia.
Tardive dystonia (Kang et al. 1988; Sethi et al. 1990;
Wojcik et al. 1991; Sachdev 1993; Raja 1995) and tardive
akathisia (Barnes and Braude 1985; Burke et al. 1989;
Lang 1994; Sachdev 1995c) may be atypical variants of
TD. Classifying and determining the treatment response
for these syndromes remain difficult. Signs and symptoms
seen in the acute forms of these disorders occur after
chronic exposure or with dose reduction (i.e., withdrawal)
and can coexist with TD or the acute forms of these tardive syndromes (Casey 1991, 1995). Thus, prediction of
response to treatment interventions is difficult, and clini-
570
T D . This side effect refers to a syndrome of

choreoathetoid movements that occurs after the chronic
use of antipsychotic medications. These movements can
affect any body part, so clinical presentation may include
orofacial dyskinesias (chewing, lateral jaw movements,
lip smacking and puckering, vermicular writhing and protrusions of the tongue, grimacing, forehead wrinkling, eye
blinking, and blepharospasm); choreoathetosis of the fingers, arms, feet, legs, and trunk; and occasionally irregular breathing or swallowing (Casey 1991, 1995; Rich and
Radwany 1994; Kruk and Sachdev 1995). Older patients,
women, and patients with diabetes seem to be at greater
risk of TD (Casey 1995). Psychiatric diagnosis may influence TD incidence, with affective disorders, especially
depression, increasing vulnerability (Wyatt 1996). Though
initial epidemiological reports did not demonstrate the
expected relationship between TD and medication exposure, subsequent work has shown a positive correlation
between medication use and TD incidence, with about 5
percent new cases per year (Kane et al. 1984), with an
overall rate of about 20 percent to as high as 50 percent in
the elderly (Casey 1995).
Clinicians should therefore not prematurely conclude

that a patient will be intolerant of neuroleptic medications
because of seizures, as this risk can be minimized through
choice of medication, dosage reduction, and use of anticonvulsants (Itil 1970; Cold et al. 1990; Marks and
Luchins 1991).
Cognitive Dysfunction and Sedation. The literature on
the cognitive effects of antipsychotic medications is
extremely complicated. As expected, the many areas of
cognitive functioning differ in responsiveness to antipsychotic medications. In addition, some aspects of cognitive
function should improve with recovery from psychosis,
obscuring the observation of areas that might deteriorate
with antipsychotic medication usage. Thus, depending on
when a patient is tested for which area of cognition,
investigators claim no effect, improvement or impairment,
in cognition with antipsychotic medications (Medalia et
al. 1988; Hindmarch 1994; King 1994; Verdoux et al.
1995). In reviewing this topic, Goff and Shader (1995)
remind the clinician that anticholinergic medications can
cause memory problems and that the use of these medications to treat EPS presents a greater risk of cognitive
impairment than is posed by antipsychotic medications
with low levels of anticholinergic activity.
Sedation secondary to medication can be regarded as
either daytime somnolence or a state in which sleep is
facilitated day or night. This side effect may be hard to
distinguish from the mental slowing seen in some patients
with cognitive impairment. The traditional antipsychotics
have varying propensities to cause sedation, with lowpotency medications the worst offenders. This side effect
can be a major source of neuroleptic intolerance, affecting
how patients feel and their ability to work and function.
Unfortunately, despite improved EPS profiles, clozapine
especially but also olanzapine to a modest degree are
sedating (Meltzer 1995; Beasley et al. 19966).
Nonneurological Side Effects

The nonneurological side effects of antipsychotic medications include both central and peripheral actions, but are
manifest as symptoms in areas not directly related to
motor or direct CNS functions.
Sexual Dysfunction and Related Problems. Sexual
side effects can make antipsychotic medications particularly intolerable. These problems include erectile and
ejaculatory difficulties, hyperprolactinemia with galactorrhea or menstrual changes, gynecomastia, and priapism.
Erectile and ejaculatory problems. Difficulty in
sexual arousal and trouble with erections and ejaculation
571
Seizures. Although less common than the EPS, seizures

can occur in patients receiving antipsychotic medications.
Occasionally clinicians advise avoidance of antipsychotic
medications because of their potential to lower the seizure
threshold. The practical risk of provoking seizures seems,
however, to be low0.5 to 0.9 percent, depending on
dose. Clozapine is the exception, with incidence rates
often higher than the frequently cited rate of 3 percent; the
cumulative risk over 3.8 years has been estimated at 10
percent (Itil 1970; Cold et al. 1990; Marks and Luchins
1991; Devinsky and Pacia 1994; Toth and Frankenburg
1994; Welch et al. 1994; Wilson and Claussen 1994; Goff
and Shader 1995).
Before the development of clozapine, the risk of
seizures seemed to be greatest for aliphatic phenothiazines, such as chlorpromazine, with some exceptions
(Itil and Soldatos 1980; Cold et al. 1990; Marks and
Luchins 1991). Thioxanthenes and butyrophenones seem
to lower the seizure threshold more than piperazine phenothiazines, and molindone may be less problematic than
other drugs (Itil and Soldatos 1980). Other reviewers have
concluded, however, that the use of haloperidol, a butyrophenone, is preferred when trying to avoid antipsychotic-associated seizures (Garcia and Alldredge 1994).
The seeming inconsistency in these findings, we suspect,
is a function of the overall low seizure risk for antipsychotic medications other than clozapine and chlorpromazine.
Dosage is a risk factor for seizures (Cold et al. 1990;
Marks and Luchins 1991; Garcia and Alldredge 1994),
suggesting that the problem can be addressed by prescription of lower doses. Though seizures have occurred in
patients on low doses of clozapine, this occurrence may
be a function of the initial rate of titration, as higher
dosage during maintenance seems to be associated with
clozapine seizures (Devinsky and Pacia 1994; Pacia and
Devinsky 1994; Toth and Frankenburg 1994). Changes in
electroencephalograms (EEGs) with clozapine have been
correlated with blood levels of the drug (Haring et al.
1994), and monitoring EEGs may assist in reducing the
risk of seizures (Welch et al. 1994). Clozapine doses that
yield blood levels up to 600 ng/ml may be sufficient for
clinical effect with a lower risk of seizure compared with
blood levels above that point (Marks and Luchins 1991).
In addition, clozapine seizures can be managed with
adjunct anticonvulsants, such as phenytoin or valproate
(Pacia and Devinsky 1994; Toth and Frankenburg 1994;
Wilson and Claussen 1994), though one investigator questioned whether anticonvulsant use might hinder clozapine
efficacy (Wilson 1995). Carbamazepine should be
avoided because of the neutropenia and agranulocytosis
risk associated with this drug.
T.E. Hansen et al.
Urinary Problems. Antipsychotic medications may be

associated with either urinary incontinence or retention, as
reviewed by Pollack et al. (1992). Incontinence can occur
with or without an underlying anatomical predisposition,
may be stress-induced or spontaneous, and may be related
to the alpha-adrenergic blockade. Central dopaminergic
effects may also be important. Although all antipsychotics
can cause incontinence, agents with prominent adrenergic
572
Hyperprolactinemia. Dopaminergic stimulation of

D 2 receptors in the pituitary inhibits the release of prolactin. Thus, treatment with antipsychotic medications,
which are D 2 antagonists, may result in increased prolactin secretion (Rubin and Hays 1980; Goff and Shader
1995). This hyperprolactinemia can then cause decreased
sexual interest, anorgasmia, oligomenorrhea/amenorrhea,
and galactorrhea (Smith 1992; Gingell et al. 1993; Goff
and Shader 1995; Wesselmann and Windgassen 1995).
Bromocriptine may be effective in reversing the increased
levels of prolactin and restoring regular menses in some
women (Smith 1992). Interestingly, although side effects
are usually seen as contributing to neuroleptic intolerance,
43 percent of patients with galactorrhea reported favorable feelings (e.g., confirming their femininity) about the
condition (Wesselmann and Windgassen 1995). Other
patients, however, disliked this side effect. The newer
antipsychotic medications vary in their propensity to raise
prolactin levels. Risperidone causes dose-related elevations, whereas clozapine does not; prolactin levels do not
change significantly with olanzapine and sertindole in
relation to placebo (Beasley et al. 19966; van Kammen et
al. 1996).
Gynecomastia. Only rarely can gynecomastia be
attributed to antipsychotic use. In a review of five
reported cases, the authors noted that two patients had
liver disease that could have been the primary cause
(Thompson and Carter 1993). They also reported that prolactin levels do not correlate with the presence of gynecomastia. The authors concluded that this lack of correlation, coupled with the small number and poor quality of
case reports, argues against an antipsychotic etiology for
gynecomastia (Thompson and Carter 1993).
Priapism. Patients who have had painful protracted
erections (priapism) related to antipsychotic medication
use may become reluctant to take antipsychotic medications in the future. This side effect, which was initially
observed with thioridazine and chlorpromazine (Goff and
Shader 1995), is associated with several other antipsychotics including risperidone (Ernes and Millson 1994;
Tekell et al. 1995; Hoffman et al., submitted for publication), haloperidol (Morera et al. 1988), and clozapine
(Rosen and Hanno 1992). The etiology is thought to be
alpha-adrenergic blockade.
in patients receiving antipsychotic medications are wellknown problems (Goff and Shader 1995). Clinicians and
patients may, however, be reluctant to discuss these concerns. In a study comparing medicated schizophrenia
patients on depot antipsychotics with unmedicated schizophrenia patients and normal controls, a high degree of
dysfunction was demonstrated using structured interviews
(Aizenberg et al. 1995). Although medicated and unmedicated schizophrenia patients revealed a decrease in
desire, both groups had increased masturbatory behaviors
and decreased degree of erection and ease of arousal to
erection. Loss of erection during intercourse and premature ejaculation increased in both patient groups. The incidence of retarded ejaculation was not increased in the
medicated group, which was receiving high-potency
antipsychotic medications.
The complicated basis for sexual dysfunction is
reviewed in detail elsewhere (Segraves 1989; Pollack et
al. 1992; Gitlin 1994). Many central and peripheral neurotransmitter systems that are affected both by psychotic illness and by antipsychotic medications have been implicated in normal sexual function. Sexual dysfunction can
be caused by direct or indirect neurotransmitter effects.
Thus, if dopaminergic activity supports sexual interest
and arousal, dopamine-blocking drugs could diminish this
function. Dopamine blockade also elevates prolactin levels, an additional contributor to decreased sexual interest,
and thus also affects sexual functioning indirectly.
Clozapine, with its reduced dopamine blockade, would be
expected to have less impact on this aspect of sexual function (Gitlin 1994). However, adrenergic influences are
thought to be especially important in erectile and ejaculatory functions (Segraves 1989; Pollack et al. 1992; Gitlin
1994), so medications that have moderate alpha-adrenergic antagonism, such as clozapine, can contribute to sexual dysfunction based on these qualities. Predicting what
influence an antipsychotic medication will have on sexual
function is further complicated because serotonin antagonism may facilitate sexual activity and cholinergic agents
may influence other neurotransmitters that are involved
more directly in sexual functioning (Segraves 1989;
Pollack et al. 1992; Gitlin 1994).
In fact, all traditional antipsychotic medications have
been associated with some sexual dysfunction, with thioridazine probably the most problematic because it causes
retrograde ejaculation (Pollack et al. 1992; Goff and
Shader 1995). Normal function returns when the drug is
discontinued. Sertindole causes a potentially troubling
reduction in the volume of ejaculate in 20 percent of male
patients. This decrease is not due to retrograde ejaculation, but the exact mechanism is unclear (van Kammen et
al. 1996). In patients with preexisting concerns about sexual function, these side effects can be truly intolerable.
clinical elevations in liver function tests, that these abnormalities may return to normal despite continuation of the
medication, and that chronic mild liver function test
abnormalities are unlikely to result in serious liver damage. Among the newer antipsychotic medications, olanzapine treatment led to mild, reversible increases in liver
enzymes in some patients (Beasley et al. 1996a, 19966).
Symptomatic patients or those with large elevations in
enzymes should have antipsychotic medication discontinued and receive a thorough hepatic evaluation (Leipzig
1992).
blocking activities, such as the low-potency phenothiazines, are the more likely offenders. If lowering
dosage or switching the type of medication is not successful, an anticholinergic medication like oxybutinin or benztropine or a dopamine agonist like amantadine may be
useful. Urinary retention can occur with all antipsychotics
but is associated most strongly with the more anticholinergic agents, because the detrusor muscle of the bladder is
under cholinergic control (Pollack et al. 1992).
Ocular and Dermatological Problems.

Dermatological side effects. These side effects
from antipsychotic medications include photosensitivity
and unusual cutaneous pigmentation (seborrheic dermatitis could also be considered a dermatological problem,
though it is part of the drug-induced Parkinsonian syndrome). The occurrence of a blue- to slate-colored pigmentation in up to 3.4 percent of chronically medicated
psychotic patients caused concerns in the past (Greiner
and Berry 1964; Ban and Lehmann 1965; Ananth et al.
1972; Ban et al. 1985), but based on the infrequency of
recent citations is not considered a modern source of neuroleptic intolerance. This problem seemed to occur primarily in patients treated with high doses of chlorpromazine for extended periods (Greiner and Berry 1964;
Ban and Lehmann 1965; Ananth et al. 1972; Ban et al.
1985). Its limited reversibility led to attempts to treat the
syndrome with depigmenting agents D-penicillamine and
ascorbic acid, although the latter was not effective
(Gibbard and Lehmann 1966). Alternatively, the pigmentary changes were dealt with by substituting different
antipsychotic medications (Ewing and Einarson 1981;
Thompson et al. 1988; Lai et al. 1993). Several pathophysiological mechanisms may be responsible for this
condition: An inflammatory response to chlorpromazine
might cause increased melanin deposition, potentially a
direct cause of change in skin color. Also, melanin may
act as a scavenger of purple- to blue-colored free radicals
formed by ultraviolet light acting on chlorpromazine
(Satanove 1965).
Photosensitivity reactions ranging from erythema
(sunburn, sometimes severe) to urticarial and maculopapular eruptions (Satanove 1965; Goff and Shader
1995) can occur with the use of antipsychotic medication.
Recent data on the frequency of photosensitivity are relatively unavailable (Whitworth and Fleischhacker 1995),
although it has been reported for one patient on clozapine
(Howanitz et al. 1995). Photosensitivity reactions can
reflect either a photoallergic reaction (Satanove 1965) or
be a consequence of free radical formation (Satanove
1965; Chignell et al. 1985; Goff and Shader 1995). If it is
573
Hepatic Dysfunction. Concern over the hepatic side

effects of antipsychotic medications dates to early experience with an increased incidence of cholestatic jaundice
from use of chlorpromazine, which may have been associated with early impurities in the drug (Bristow and Hirsch
1993). Other authors did not cite impurities as the cause
of that increased incidence, but noted that chlorpromazine
and other antipsychotic medications can both act as direct
hepatotoxins and affect bile flow (Sherlock 1989; Leipzig
1992). The formation of toxic free radical metabolites
may be required in the pathophysiology of cholestatic
jaundice, as subjects capable of effective sulfoxidation did
not seem to be vulnerable to this side effect (Watson et al.
1988). Direct comparison of present and past incidence
rates is not available, although rates of hepatic dysfunction seemed high with chlorpromazine in early reports1
to 2 percent with jaundice, 20 to 42 percent when mild
cases were included (Dickes et al. 1957; Bartholomew et
al. 1958; Gupta et al. 1962)and were low (0.13%) in a
recent report (Derby et al. 1993). Rare cases of cholestatic
liver disease have been reported with haloperidol (Fuller
et al. 1977; Dincsoy and Saelinger 1982). Sherlock (1989)
reports that cholestasis will affect 1 to 2 percent of
patients on chlorpromazine, independent of dose, and
often in the first 4 weeks of treatment. Alkaline phosphatase levels rise, sometimes without other biochemical
changes. Eosinophilia may also occur, suggesting an idiosyncratic or allergic basis in some cases (Sherlock 1989).
Usually recovery is complete after medication discontinuation (Sherlock 1989).
To the extent that antipsychotic medications can act
as direct hepatotoxins, perhaps through free radical formation, elevations in transaminases will be seen in some
patients with antipsychotic use (Sherlock 1989). However,
these enzyme elevations only rarely require consultation
with a gastroenterologist. Despite the general expectation
that more exposure to hepatotoxins could be associated
with hepatic necrosis (Sherlock 1989), an early study
noted that transaminase levels can rise without producing
any observed pathology on liver biopsy (Bartholomew et
al. 1958), suggesting presumably benign changes in membrane permeability. Further, Leipzig (1992) reports that
most patients who receive chlorpromazine develop sub-
T.E. Hansen et al.
doses of 800 mg/day or lower (Oshika 1995). However,

clinicians should be attentive to complaints of visual
change regardless of the dose and type of medication,
since lower doses and the use of other antipsychotics have
been associated with this degenerative retinopathy
(Mitchell and Brown 1995; Oshika 1995).
The final two ocular side effects are trouble with
accommodation and angle-closure glaucoma. Impaired
accommodation, or cycloplegia, is associated with pupillary dilatation (mydriasis) and is a function of anticholinergic effects (Oshika 1995). Thus, it varies with the
antipsychotic used, as well as with the use of antiParkinsonian medications to counter EPS. Tolerance may
occur, and if not, a topical cholinergic agonist (pilocarpine) may be useful (Oshika 1995). Angle-closure
glaucoma occurs with mydriasis in patients with physiologically narrow anterior chamber angles and so is a
greater risk for patients taking medications with strong
anticholinergic effects. Symptoms include blurred vision,
pain, lacrimation, lid edema, and such systemic effects as
nausea and vomiting. Treatment with topical anticholinesterase and parasympathomimetic drops or surgical
intervention must be immediate to prevent permanent loss
of vision from increased intraocular pressure (Oshika
1995).
Cardiac Effects. Cardiac side effects may follow from
direct cardiac effects or from other changes affecting the
cardiovascular system, such as hypotension and anticholinergic-induced tachycardia.
Orthostatic hypotension. This condition occurs
commonly with the use of typical low-potency antipsychotic medications and is presumably related to coincident alpha-adrenergic blockade (Goff and Shader 1995)
with a possible contribution from the inhibition of central
pressor reflexes (Lipscomb 1980). Patients may develop
tolerance to orthostasis, and a gradual upward titration of
dosage may reduce the risk of hypotension in patients
treated with clozapine or other antiadrenergic drugs (Goff
and Shader 1995).
Given its frequency, this side effect is more problematic than the potentially more serious and life-threatening
direct cardiac effects. Achieving a lower incidence of
orthostasis is one reason to prescribe higher potency
antipsychotic medications in older patients (Branchey et
al. 1978). Orthostatic hypotension could contribute to the
occurrence of hip fractures when antipsychotic medications with this propensity are used in the elderly. One
study found that elderly patients taking antipsychotic
medications had a twofold increase in risk of hip fracture
(Ray et al. 1987). The authors speculate that sedation or
adrenergic blockade (i.e., hypotension) or both could be
574
an allergic reaction, one would expect an incubation

period and occurrence with either low or high dosage
(Satanove 1965). Patients should be warned about this
possible side effect so that sun precautionsavoidance,
sun blockscan be taken.
Pseudolymphoma formation seems to be a very rare
dermatological side effect seen in several patients treated
with thioridazine (Aguilar et al. 1992). This reactive condition most likely is caused by B-cell infiltration at a site
of inflammation.
Ocular problems. Ocular side effects of antipsychotic medication range from inconvenient to vision
threatening. Patients should be encouraged to seek routine
eye care, and complaints of visual changes should be
attended to properly. To the extent that some of these syndromes involve cutaneous structures or pigment deposition, they are often considered to be related to the dermatological effects. There may be differences in some
pathophysiological mechanisms, however (Lai et al.
1993). Ocular side effects include pigment deposition in
the cornea and lens, non-pigment-related corneal changes,
cataracts, pigmentary retinopathy, corneal edema, difficulty in accommodation, and angle-closure glaucoma
(Oshika 1995). The pigment deposition in the cornea and
lens seems to be influenced by exposure to light, is dose
dependent, and involves granular deposits similar to those
seen in the skin with chlorpromazine use (Lai et al. 1993;
Oshika 1995). Although skin changes have been associated most clearly with chlorpromazine, ocular pigment
deposition can occur with other antipsychotics (Goff and
Shader 1995). Pigment deposits and keratopathy without
pigment deposits (e.g., lines and streaks in the cornea) do
not affect visual acuity (Oshika 1995). Although pigment
deposition may not cause ordinary cataracts in patients on
antipsychotic medication, cataracts occur at a higher frequency in these patients (Oshika 1995) and do impede
vision. Cataracts may be a consequence of a series of
reactions starting with lens protein aggregation and eventually increased calcium accumulation (Kamei et al.
1994). Rarely, corneal edema can occur and also threaten
vision (Oshika 1995).
Pigmentary retinopathy is the best-known retinal side
effect associated with antipsychotic medication use.
Pigment is deposited spreading from the periphery to the
central retina, causing the loss of peripheral vision,
decreased night vision, scotomata, and eventually blindness. If it is discovered early and medication is stopped,
visual acuity may improve, but the pigmentary changes
are thought to be permanent and may progress even after
medication discontinuation (Meredith et al. 1978). Most
cases have been associated with the use of thioridazine in
doses above 1,000 mg/day, with generally safe use at
responsible. Given that 44 of 138 patients received

haloperidol, the possible contribution of drug-induced
Parkinsonism should also be considered. Haloperidol and
thioridazine use were associated with 2.2-fold increases in
risk, whereas chlorpromazine had a 1.8-fold increase (Ray
et al. 1987).
The newer antipsychotic medications also cause
orthostatic hypotension, as expected from their antagonism of alpha-adrenergic receptors. Clozapine, risperidone, and sertindole in particular cause orthostasis.
Clozapine requires a very gradual upward dosage titration, whereas risperidone and sertindole are best initiated
over 3 and 10 days, respectively. Olanzapine does not
potentially antagonize adrenergic receptors and does not
cause orthostasis, although some patients complain of
dizziness (Beasley et al. 19966).
Anticholinergic side effects. These side effects are
caused by many antipsychotic medications. Thus, tachycardia can occur because vagal innervation of the sinus
node is cholinergic and inhibitory. Tachycardia may be
clinically significant, for instance if a patient had angina,
but it is usually benign.
Direct cardiac effects. These effects of antipsychotic medications can be observed on electrocardiogram
(EKG) tracings in as many as 25 percent of phenothiazine-treated patients (Thomas 1994). They are largely
attributed to quinidinelike effects and include QT prolongation, abnormal T-wave morphology or large U waves,
and widening of the QRS complex (Branchey et al. 1978;
Lipscomb 1980; Thomas 1994). Although a quinidinelike
drug should act as an antiarrhythmic agent, the combination of the increased ventricular excitability with slowed
conduction rates yields a net proarrhythmogenic state at
higher blood levels. The dose dependence of these effects
has been demonstrated for thioridazine (Yoon et al. 1979;
Thomas 1994), the antipsychotic most associated with
arrhythmias and EKG changes (Thomas 1994; Buckley et
al. 1995). Prolongation of the QT interval makes the torsade de pointes arrhythmia a particular risk for patients
receiving thioridazine and other antipsychotic medications (Roden 1993; Thomas 1994). In this ventricular
tachyarrhythmia, the ventricular complexes are polymorphic, and because the prolonged QT interval sets the stage
for this disorder, standard antiarrhythmic agents that cause
QT prolongation cannot be used (Kemper et al. 1983;
Wilson and Weiler 1984; Kiriike et al. 1987; Roden
1993). Potentially lethal because its onset is sudden, it is
difficult to treat, and it can result in ventricular fibrillation, torsade de pointes may be treated with isoproterenol
or cardiac pacing (Kemper et al. 1983; Wilson and Weiler
1984; Kiriike et al. 1987; Roden 1993). Clinicians should
be aware of the risk for this syndrome not just with thio-
ridazine, but with other antipsychotic medications as well.

Chlorpromazine has quinidinelike qualities, and pimozide
and haloperidol have been associated with cases of torsade de pointes (Thomas 1994; Faigel et al. 1995; Goff
and Shader 1995). Sertindole causes small dose-related
increases in the QT interval, making it another medication
in which this QT effect must be considered (van Kammen
et al. 1996).
Miscellaneous Effects. A variety of other side effects

occur with antipsychotic medication use. Some may be
difficult to tolerate, but others are rare and not likely to
influence either patients or clinicians in using or prescribing antipsychotics. Weight gain can be a problem, especially with low-potency phenothiazines (Goff and Shader
1995) and clozapine (Meltzer 1995). Initial experience
with risperidone, sertindole, and olanzapine indicates that
patients will be troubled by weight gain with these new
antipsychotics as well (Beasley et al. 19966; van Kammen
et al. 1996). A high proportion of centrally distributed
obesity, a purported measure of greater health risk than
simple weight gain, was reported in one study of patients
treated with a variety of antipsychotic medications
(Stedman and Welham 1993). Agranulocytosis is the most
dangerous side effect seen with the use of clozapine and
obviously establishes intolerance for affected patients
(Kane et al. 1988a; Kane and Freeman 1994). Hyponatremia can occur in patients receiving antipsychotic medication, presenting the question of whether the patient is
exhibiting psychogenic polydipsia or the syndrome of
inappropriate antidiuretic hormone secretion. Hyponatremia apparently can occur with use of a variety of
high- and low-potency antipsychotic medications (Ellinas
et al. 1993; Goff and Shader 1995). Ischemic colitis has
575
Respiratory Symptoms. Respiratory dyskinesias can

occur as part of the syndrome of TO, as noted above. One
group (Joseph et al. 1996) examined the risk of death
from asthma associated with antipsychotic use. They concluded that patients with asthma who use antipsychotic
medications are at greater risk of death than other asthma
patients, a finding not replicated for other psychotropic
drugs. However, the association was actually for patients
who had decreased the dosage or discontinued their
antipsychotic medication, raising an alternative conclusion that patients who are presumably increasingly psychotic because of medication discontinuation become
more vulnerable to complications from their medical conditions. We concur with Davies (1996) and Levy (1996)
that the results of this study suggest the need for better
care of physical illnesses in patients taking antipsychotic
medications.
T.E. Hansen et al.
Neuroleptic Intolerance: Side Effects

and Compliance
The foremost concern regarding neuroleptic intolerance is
that patients will not receive the therapeutic benefits possible from antipsychotic medications. When neuroleptic
medications cannot be tolerated by a patient, noncompliance seems likely if the patient's physician has not
already stopped the medication. Evidence for this noncompliance was established more than 20 years ago. Van
Putten demonstrated that EPS were more common in
"drug-reluctant" patients and that dysphoric reactions to
drugs were associated with EPS (Van Putten 1974, 1975).
This work has been replicated more recently, with patients
who had dysphoric responses to antipsychotic medication
having poorer outcomes (Awad and Hogan 1994).
To the extent that EPS are an important source of
noncompliance and new antipsychotics have few or no
EPS, future patients should have less trouble with neuroleptic intolerance. However, new drugs still have side
effects that could lead to noncompliance. The occurrence
of agranulocytosis, sedation, orthostasis, weight gain, and
lowered seizure threshold makes taking clozapine difficult. For risperidone, orthostatic hypotension, weight
gain, hyperprolactinemia, and erectile difficulties could
influence patient acceptance, as could EPS if the dosage
cannot be kept below the individual patient's threshold for
EPS (Casey and Hansen 1995). Orthostatic hypotension,
QT prolongation, reduced ejaculatory volume, weight
gain, and nasal congestion may be problematic for
patients prescribed sertindole. And with olanzapine,
patients may be bothered by sedation, weight gain, and
anticholinergic side effects (Beasley et al. 19966). Still,
these medications seem to be better tolerated than traditional antipsychotics (Gerlach and Peacock 1994; Kane
and Freeman 1994; Kerwin 1994; Lindstrom 1994;
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Acknowledgments
This work was supported in part by funds from the
Veterans Affairs Medical Center to Drs. Hansen and
Casey, by USPHS grant MH-52351 to Dr. Hoffman, and
MH-36657 to Dr. Casey from the National Institute of
Mental Health.
The Authors
Thomas E. Hansen, M.D., is Co-Manager, Inpatient
Psychiatry, Portland Veterans Affairs Medical Center, and
Associate Professor, Department of Psychiatry, Oregon
Health Sciences University. Daniel E. Casey, M.D., is
Chief, Psychiatric Research and Psychopharmacology,
Portland Veterans Affairs Medical Center, and Professor
of Psychiatry and Neurology, Oregon Health Sciences
University. William F. Hoffman, Ph.D., M.D., is Staff
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Neuroleptic Intolerance

by Thomas E. Hansen, Daniel E. Casey, and William F. Hoffman

This article reviews antipsychotic medication side

Reprint requests should be sent to Dr. T.E. Hansen, Portland VA

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effective in treating psychosis while causing low rates of

Schizophrenia Bulletin, Vol. 23, No. 4, 1997

T.E. Hanscn ct al.

Table 1. Side-effect profile of typical

Fortunately, acute dystonic reactions respond rapidly

Note.EPS - extrapyramidaJ side etfects.

Neurological Side Effects

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spasm. Other problems can develop secondary to dystonic

patient factors that interact with drug characteristics to

Schizophrenia Bulletin, Vol. 23, No. 4, 1997

Akathisia occurs early in the course of antipsychotic

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neuroleptics (i.e., cause acute EPS) is targeted at reducing

Schizophrenia Bulletin, Vol. 23, No. 4, 1997

T.E. Hansen et al.

The risk of TD may influence some clinicians to

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T D . This side effect refers to a syndrome of

Schizophrenia Bulletin, Vol. 23, No. 4, 1997

Clinicians should therefore not prematurely conclude

Nonneurological Side Effects

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Seizures. Although less common than the EPS, seizures

Schizophrenia Bulletin, Vol. 23, No. 4, 1997

T.E. Hansen et al.

Urinary Problems. Antipsychotic medications may be

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Hyperprolactinemia. Dopaminergic stimulation of

Schizophrenia Bulletin, Vol. 23, No. 4, 1997

Ocular and Dermatological Problems.

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Hepatic Dysfunction. Concern over the hepatic side

Schizophrenia Bulletin, Vol. 23, No. 4, 1997

T.E. Hansen et al.

doses of 800 mg/day or lower (Oshika 1995). However,

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an allergic reaction, one would expect an incubation

Schizophrenia Bulletin, Vol. 23, No. 4, 1997

responsible. Given that 44 of 138 patients received

ridazine, but with other antipsychotic medications as well.

Miscellaneous Effects. A variety of other side effects

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Respiratory Symptoms. Respiratory dyskinesias can

Schizophrenia Bulletin, Vol. 23, No. 4, 1997

T.E. Hansen et al.

Neuroleptic Intolerance: Side Effects

Adler, L.A.; Angrist, B.; Reiter, S.; and Rotrosen, J.

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Meltzer 1995). Further, a study in which patients rated the

been reported with antipsychotic use, presumably after

Schizophrenia Bulletin, Vol. 23, No. 4,1997

olanzapine trial. Neuropsychopharmacology, 14:111-123,

Aizenberg, D.; Zemishlany, Z.; Dorfman-Etrog, P.; and

Branchey, M.H.; Lee, J.H.; Amin, R.; and Simpson, G.M.

Ananth, J.V.; Ban, T.A.; Lehmann, H.E.; and Rizvi, F.A.

Bristow, M.F., and Hirsch, S.R. Pitfalls and problems of

outcome. Ada Psychiatrica Scandinavica, 89(Suppl.

Casey, D.E. Neuroleptic drug-induced extrapyramidal