Antipsychotic medications are generally divided into two
categories: first generation (typical) and second generation (atypical). The
main difference between the two types of antipsychotics is that the first
generation drugs block dopamine and the second generation drugs block dopamine
and also affect serotonin levels. Evidence suggests that some of the second
generation drugs have milder movement- related side-effects than the first
generation drugs.
Both categories of drugs work equally well overall, although no
drug or type of drug works equally well for everyone who takes it. When the
same drug is given to a group of people, one third of that group will find that
it works well; another third will find that the drug helps only with some
symptoms; and the final third will find that it does not help at all. For this
reason, people may need to try different antipsychotics before finding the one
that works best for them.
Most of these drugs are given in tablet form, some are liquids and
others are given as injections. Some are available as long-lasting (depot)
injections, which may be given anywhere from once a week to once a month.
Antipsychotics are often used in combination with other medications
to treat other symptoms of mental health problems or to offset side-effects.
Most people who take antipsychotics over a longer term are now
prescribed the second generation (also called atypical) drugs.
2.1 Second generation
(atypical) antipsychotics
Medications available in this class include risperidone
(Risperdal)*, quetiapine (Seroquel), olanzapine (Zyprexa), ziprasidone
(Zeldox), paliperidone (Invega), aripiprazole (abilify) and clozapine
(clozaril). clozapine is exceptional in that it often works even when other
medications have failed; however, because it requires monitoring of white blood
cell counts, it is not the first choice for treatment. The second generation
antipsychotics are usually the first choice for the treatment of schizophrenia.
Although they may not be officially approved for these other uses, they are
sometimes used in the treatment of mood and anxiety disorders, such as bipolar,
posttraumatic stress and obsessive-compulsive disorders.
Some possible side-effects of this type of medication include dry
mouth, dizziness, blurred vision and, rarely, seizures. The following table
lists other side-effects of second generation antipsychotics and shows which
drugs are most likely to least likely to have these effects.
*medications are referred to in two ways: by their generic name
and
by their brand or trade names. Brand names available in Canada appear here in brackets.
by their brand or trade names. Brand names available in Canada appear here in brackets.
Table: showing the side effect of second generation antipsychotics
|
Side-effects of second generation antipsychotics
|
Drugs most likely to least likely to
have these effects
|
|
Weight gain, diabetes
|
clozapine > olanzapine > quetiapine > risperidone >
ziprasidone, aripiprazole
|
|
movement effects (e.g., tremor, stiffness, agitation)
|
risperidone > olanzapine, quetiapine, ziprasidone,
aripiprazole > clozapine
|
|
Sedation (e.g., sleepiness, low energy)
|
clozapine, olanzapine and quetiapine > risperidone,
ziprasidone, aripiprazole
|
|
Decreased sex drive and function, missed periods, discharge from
breasts
|
risperidone > olanzapine, quetiapine > clozapine,
ziprasidone
|
2.1.1 Side-effects of the typical antipsychotics
Most of the side effects of the typical
antipsychotics can also be encountered with the atypical agents; however, they
are less frequent and generally less severe.
Weight gain is problem in
schizophrenia and other mental disorders, in part, because of poor eating
habits and lack of exercise. However, the atypical antipsychotics exacerbate
this problem. A meta-analysis (Allison and Casey, 2001) estimated that over a
10 week period the mean increase was as follows:
1) clozapine 4.45 kg
2) olanzapine 4.15 kg
3) risperidone 2.1 kg (quetiapine
probably similar)
4) ziprasidone 0.04 kg (aripiprazole
probably similar).
The prevalence of type 2 diabetes in
people with schizophrenia is double that of the general population. Over recent
years there has been concern this may be a direct result of atypical
antipsychotic treatment. As the atypical antipsychotics are the most effective
component in the medical management of psychotic disorders, this question was
soberly examined. An association between schizophrenia and diabetes has been
recognized for over a century. Risk factors for diabetes include poor overall
health, lifestyle and level of access to heath care. Atypical antipsychotics
are associated with weight gain, but there is no evidence for an intrinsic role
for the antipsychotics in the aetiology of diabetes.
As this issue has been brought to the attention
of clinicians, they have a responsibility to monitor the diabetes risk factors
of patients (Poulin et al, 2005).
Hyperlipidemia (raised
cholesterol and triglycerides) appears to be associated with the dibenzodiazepine-derived
antipsychotics (clozapine, olanzapine and quetiapine).
QTc interval prolongation has been a
matter of concern. The average QTc interval in healthy adults is about 400
msec, and a QTc interval of 500 msec or more is a risk factor for torsade de
pointes (a ventricular arrhythmia which can lead to syncope, ventricular
fibrillation and sudden death). One study found the following prolongations:
1) ziprasidone 20.3 ms
2) quetiapine 14.5 ms
3) risperidone 11.6 ms
4) olanzapine 6.8 ms
5) haloperidol 4.7 ms
Myocarditis and cardiomyopathy are rare (0.015-0.188 %; Merrill et al, 2005) side effects of clozapine
therapy.
Recommendations for the
monitoring/management of the side effects of the atypical antipsychotics have
been provided (Marder et al, 2004). However, further work is required. When
weight gain is anticipated (clozapine, olanzapine, quetiapine and risperidone)
weight and BMI should be recorded. Nutritional and life style (exercise) advice
is recommended. With excessive weight gain a change to another agent may be
considered. When diabetes is anticipated (clozapine and olanzapine in
particular) the weight is to be monitored and laboratory measures (eg fasting
blood glucose) are indicated. When hyperlipidemia is anticipated (clozapine,
olanzapine and quetiapine) serum cholesterol and triglycerides may be
monitored. When QTC prolongation is anticipated (ziprasidone, particularly),
EEG monitoring is recommended in cases of increased cardiac risk (known heart
disease, syncope, family history of early sudden death). Myocarditis has been
associated with clozapine and clozapine clinics have specialized screening
procedures.
2.1.2 Individual atypical
antipsychotics
As in all branches of medicine, if a
disorder cannot be controlled with standard doses of a particular agent, first
the dose is increased judiciously, and if the desired result remains evasive,
another agent is trialled. The management of psychosis is difficult.
Fortunately we have a range of atypical antipsychotics; while they have some
similar actions, they come from range chemical classes, and all have particular
advantages. A series of trials may be necessary for the best possible outcome.
Clozapine: Clozapine is often effective in treating
schizophrenia which has been unresponsive to all other antipsychotics. It is
unique in causing neutropenia (potentially fatal) in 1-2% of patients. Thus,
clozapine is reserved for severe otherwise unresponsive psychosis, and must be
managed by specialized clinics which conduct regular (weekly for the first 18
weeks) blood tests.
Other side-effects include significant
weight gain, hypotension and tachycardia. Hypersalivation (unknown with the
typical antipsychotics) can be troublesome with clozapine (and rarely with some
other atypicals, such as olanzapine). 1% of patients experience seizures – this
does not mean clozapine must be ceased – instead, anticonvulsants are added.
This is a formidable array of side-effects; nevertheless the antipsychotic
benefits are substantial. Clozapine is also useful in the treatment of TD.
Risperidone: Risperidone is an effective antipsychotic. At high
doses (8 mg and above) it loses some of its advantages over typical
antipsychotics, insofar, as acute EPS readily appear. A major disadvantage is
the elevation of prolactin levels. A preparation which dissolves in the mouth
is available. Risperidone has an advantage over the other atypicals in that an
IMI depot (long-acting) preparation is available. This can be administered once
per fortnight during the maintenance phase, somewhat reducing compliance
problems.
Paliperidone: Paliperidone is the active metabolite of
risperidone, which was released when the patent of the parent chemical was about
to expire. It has a slightly improved side-effect profile. There is less weight
gain, but more EPS problems, and the elevation of prolactin remains
problematic. The dosing strategy is simple; one capsule enables a single daily
dose.
Recently a paliperidone depot has become
available which need only be repeated monthly (a great advantage over 2/52
injection). The monthly dose is usually 25-50 mg.
Olanzapine: Olanzapine is an effective antipsychotic which has
gained acceptance as a mood stabilizer (used in the prophylaxis of mood
disorder; Tohen et al, 2005). It has a pharmacological action and side-effect
profile similar to clozapine (except, it is not associated with blood
dyscrasia). The most troublesome side-effects are weight gain and sedation. The
risks of diabetes and hyperlipidemia need to be monitored. An occasional
side-effect, which is seen more regularly with clozapine, is hypersalivation.
Olanzapine does not elevate prolactin to a significant degree. The
sedating/calming effect of olanzapine is useful in acute disturbance.
Olanzapine has an advantage of over the other atypical medications in being
available in an IMI form for acute administration. A preparation which
dissolves in the mouth is available. A long-acting depot form is available but
because physiological response is variable, the patient must be observed for 3
hours following every injection (which is proving to be a disincentive).
Quetiapine: Quetiapine is an effective antipsychotic which has a
receptor binding profile similar to clozapine, but with relatively lower
affinity for all receptors. The side-effect profile is favourable, 75% of
respondents denying any side-effects. Sedation and hypotension are reported,
especially during the commencement phase. Weight gain, and the risk of diabetes
and hyperlipidemia need to be considered. Quetiapine has little affinity for
muscarinic receptors so that blurred vision and difficulty with micturition are
rarely problems. The rate of EPS is similar to placebo and there is no
significant elevation of prolactin. Quetiapine may cause sedation and weight
gain. (Komossa et al, 2009).
Amisulpride: Amisulpride is a useful antipsychotic which has
effects (potent antagonist) only at D2 and D3 receptors (and no effect on
serotonin receptors). At recommended doses it appears to be selective for
limbic (rather than extra-pyramidal system) receptors (Xiberas et al, 2001).
Unfortunately, when higher doses are required, EPS side-effects may become a
problem. Amisulpride is less likely to cause weight gain than the other
atypical antipsychotics, but it produces robust elevation of prolactin levels,
thus breast development and lactation in both men and women and amenorrhoea in
women may be bothersome side effects. (Komossa et al, 2009).
Aripiprazole: Aripiprazole is a recently released
antipsychotic. Rather than an antagonist of dopamine receptors, it appears to
be a high affinity partial agonist at presynaptic D2 receptors and an
antagonist at postsynaptic D2 receptors. It has little affinity for D3, D4 and
D1-like receptors, and its affinity for 5HT-2A receptors is low. There is some
alph-1 blockade and orthostatic hypotension has been reported. The efficacy
appears similar to risperidone and less than olanzapine, but the side-effect
profile appears favourable at manufacturer recommended doses, with minimal
elevation of prolactin. (Komossa et al, 2009).
However, a recent review demonstrated no
clear advantage over many other second generation antipsychotics (Khanna et al,
2013). Aripiprazole has a role as a mood
stabilizer (Keck et al, 2007).
Asenopine: Is a recently released second generation
antipsychotic, unique in being administered sub-lingualy. It appears to be an
effective antipsychotic (compared to the other available agents – but, none of
them are much good). It has a lower profile of weight gain and adverse changes
in glycemic or lipid profile (Bobo, 2013), which will be considered an
advantage. However, dose related akathisia and oral hypoaesthesia, my be
problematic.
2.2 First generation
(typical) antipsychotics
These older medications include chlorpromazine (once marketed as
Largactil), flupenthixol (Fluanxol), fluphenazine (Modecate), haloperidol
(Haldol), loxapine (Loxapac), perphenazine (Trilafon), pimozide (Orap),
trifluoperazine (Stelazine), thiothixene (Navane) and zuclopenthixol
(Clopixol).
Side-effects of this group of medications vary depending on the
drug and may include drowsiness, agitation, dry mouth, constipation, blurred
vision, and emotional blunting, dizziness, stuffy nose, weight gain, and breast
tenderness, liquid discharge from breasts, missed periods, muscle stiffness or
spasms.
2.2.1 Side-effects of typical antipsychotics
The extrapyramidal system (EPS) -
the EPS is not a side-effect of antipsychotics, but needs to be mentioned
before certain side effects. The EPS is a motor system composed of dopamine
(DA) and acetylcholine (Ach) neurons which enjoy a reciprocal relationship. In
some individuals when DA receptors are blocked, the balance in the system is
disrupted, leading to side-effects.
Acute neurological side-effects (acute
EPS effects) occur secondary to D2 receptor blockade in the EPS. These can
appear on the first day of treatment and can take various forms of involuntary
muscle spasm, particularly involving of the jaw, tongue, neck and eyes. A
dramatic form is oculogyric crisis – in which the neck arches back and
the eyes roll upward. A potentially dangerous form is laryngospasm – an
early warning sign may be the patient’s voice becoming higher pitched. (Komossa et al, 2009).
Balance has been disturbed
resulting in muscle spasm, and can be restored by acute treatment with oral or
intramuscular injection of an anti-Ach – such as benztropine (2 mg). The
response is immediate and pleasing.
Medium-term neurological
side-effects are also due to D2 blockade in the EPS. Akathisia usually
occurs within the first few day of treatment and involves either a mental
and/or motor restlessness. Mental restlessness presents as increasing distress
and agitation. Motor restlessness usually affects the lower limbs, with
shifting from one foot to the other while standing and constant crossing and
uncrossing of the legs while sitting. This is a difficult condition to manage.
Useful steps include lowering the dose of the antipsychotic (if possible),
adding diazepam or propranolol, or adding an anticholinergic (none of these
agents is dramatically effective).
Parkinsonism usually occurs
some days or weeks after the commencement of treatment. There is a mask-like
face, rigidity of limbs, bradykinesia, and loss of upper limb-swing while
walking. Tremor and festinating gait are less common. The best management is
reduction in dose of the antipsychotic (if possible) and the addition of an
anticholinergic agent. (Komossa et al,
2009).
Chronic neurological
side-effects (late EPS effects) usually occur after months or years
of continuous D2 blockade. Tardive dyskinesia (TD) manifests as
continuous choreoathetoid movements of the mouth and tongue, frequently with
lip-smacking, and may also involve the head, neck and trunk. Late EPS effects
may continue after cessation of the typical antipsychotic.
Neuroendocrine effects result
from blockade of dopamine transmission in the infundibular tract. Prolactin
levels rise, with most antipsychotic agents and extreme cases may cause
galactorrhea, amenorrhoea and infertility. (Komossa et al, 2009).
Neuroleptic malignant syndrome (NMS) is
probably due to disruption of dopaminergic function, but the mechanism is not
understood. Untreated, the mortality rate is 20%, and immediate medical
attention is mandatory. The symptoms include muscle rigidity, hyperthermia,
autonomic instability and fluctuating consciousness. Renal failure secondary to
rhabdomyolysis is a major complication and the cause of mortality.
Anticholinergic side-effects include dry mouth,
difficulty with micturition, constipation, blurred vision and ejaculatory
failure. Anticholinergic delirium is a toxic confusional state; it usually
occurs in patients taking a range of drugs directed at different symptoms, and
antipsychotics may play a role.
Histamine blockade may produce severe sedation.
Alpha adrenergic blockade may produce postural
hypotension, cardiac arrhythmias and impotence.
Dermatological side-effects include skin rash and
photosensitivity
Weight gain is common with most typical
antipsychotics.
Examples of antipsychotic medications
The oral forms of these medications are now uncommonly used.
Haloperidol produces EPS side-effects at high doses,
but the oral preparation continues to be used in small doses (e.g., 0.5-1.0 mg
bd) for brief periods for disturbed behavior in delirium and elderly patients.
The IMI preparation (e.g., 10 mg) has a place in the management of younger
disturbed people who are a danger to self or others (see later).
Zuclopenthixol continues to be used in two
IMI preparations. Zuclopenthixol acetate (50-150 mg) is useful in the
control of acute psychosis and disturbance. The beneficial effects last about 3
days. Zuclopenthixol decanoate (200-400 mg, 2-4/52) continues to command
a small place in the long-term maintenance of chronic psychotic disorders.