By Eamonn Brady MPSI
First Generation Antipsychotics
Antipsychotics are mostly used to treat the symptoms of psychosis (loss of sense of reality) in mental
health disorders such as schizophrenia and bipolar disorder. In lower doses they may be used for
sedation, sleep and easing anxiety. First generation antipsychotics (FGAs) were the first antipsychotics
developed over 50 years ago; newer antipsychotics called Second Generation Antipsychotics (SGAs)
were developed mainly since the 1990s. For the purpose of this article I will refer to First Generation
Antipsychotics as FGAs for short.
First generation antipsychotics (FGAs) available in Ireland include Chlorpromazine (Clonactil®, Largactil®),
Haloperidol (Serenace®), Trifluperazine (Stelazine®), Zuclopenthixol (Clopixol®) and flupentixol (Depixol®
Injection, Fluanxol® tablets). First generation anti-psychotics are also known as traditional antipsychotics,
older antipsychotics, neuroleptics or typical antipsychotics.
Antipsychotics have been in use since the 1950’s when chlorpromazine was first produced for use as an
antihistamine for allergies and haloperidol was produced for use as a painkiller in the 1960s; it was later
that their antipsychotic effects were realised. The main difference between first and second generation
antipsychotics relates to the ability of the medication to block the effects of dopamine on the brain. First
generation anti-psychotics cause more dopamine blockage, hence more side effects. Second Generation
Antipsychotics (SGAs) still block dopamine, but much less so than the older FGAs. SGAs also tend to
have an effect on different chemical messengers in the brain (including serotonin) compared to FGAs. By
the 1970s, the early “Second Generation Antipsychotics” such as clozapine and sulpiride were introduced.
Antipsychotics are mostly used to treat the symptoms of psychosis (schizophrenia, bipolar disorder), but
in lower doses they may be used for sedation, sleep and easing anxiety. Some newer antipsychotics also
have antidepressant effects. Excessive dopamine in certain areas of the brain is largely responsible for
symptoms of psychosis. Antipsychotics mainly block the brain’s dopamine receptors thus reducing
dopamine which leads to an antipsychotic effect. The efficacy, strength and side effect profile of different
anti-psychotics is related to which dopamine receptors are targeted (there are many different ones) and
on how many are targeted. The potency of antipsychotics is directly proportional to their ability to block
dopamine receptors in the brain. Another factor is which dopamine receptors are targeted as there are
many different ones. Antipsychotics can also have significant effects on acetylcholine, norepinephrine,
histamine and serotonin receptors and it is this that can lead to side effects.
Side effects
Common side effects of FGAs are sedation, fatigue, headaches, blurred vision, weight gain, low blood
sugar, sleep disturbances, stomach discomfort, constipation, vomiting and interference with sexual life.
Chlorpromazine has a tendency to cause skin sensitivity (rashes) when exposed to sunlight. Sunscreen
must be used if going out in strong sun while taking chlorpromazine.
Other side effects
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Extrapyramidal symptoms (EPS)
EPS are neurological disturbances in the part of the brain that controls motor coordination. EPS include
muscle tremors and muscle stiffness and rigidity. If EPS are severe the dose may need to be reduced or if
this is not possible (due to risk of relapse) then an anti-muscarinic drug such as procyclidine (Kemadrin®)
or biperiden (Akineton®) may need to be prescribed to prevent EPS.
By Eamonn Brady MPSI
Akathisia
Akathisia is kind of EPS characterized by a sense of restlessness, inability to sit still, nervousness, muscle
discomfort and agitation.
Dystonia
Dystonia is another kind of EPS; symptoms of dystonia are sudden spasm of muscles usually affecting
the tongue, jaw and neck.
Tardive dyskinesia
Tardive dyskinesia is an involuntary movement disorder which is potentially irreversible. The most
common and noticeable symptom of tardive dyskinesia include involuntary and continual movements of
the mouth, tongue and jaw and it affects approximately 1 in 20 patients prescribed antipsychotics but is
usually reversible upon discontinuation of the anti-psychotic. Other symptoms of tardive dyskinesia
include "pill-rolling" movements of the fingers, facial grimacing and other irregular movements.
Neuroleptic malignant syndrome
Neuroleptic malignant syndrome is a rare, toxic reaction to antipsychotics. The symptoms of neuroleptic
malignant syndrome include muscle stiffness, rigidity, raised body temperature, increased heart rate/blood
pressure, irregular pulse, and sweating.
Seizures
FGAs may lower seizure threshold and induce seizures in susceptible patients. This is especially an issue
for epileptics.
Heart rhythm problems
FGAs can slow electrical conduction in the heart which can trigger an irregular heart-beat (arrhythmia).
Arrhythmias show up on an electrocardiogram (ECG) as a prolonged electrical impulse known as QTcprolongation. The problem with arrhythmias is that they make a person more prone to clots, strokes and
heart attacks.
Postural hypotension
Postural hypotension is the sudden drop in blood pressure when a person stands or stretches. Postural
hypotension can cause light-headedness, dizziness and fainting. To counter this, people taking FGAs
should exercise caution when standing from the seated position or getting out of bed in the morning.
Heatstroke
Antipsychotics can disrupt the area of the brain that regulates temperature so patients prescribed
antipsychotics may be very sensitive to heat and can be more prone to heat stroke.
Selection
Selection of FGAs (e.g. chlorpromazine, haloperidol, fluphenazine and flupentixol) is influenced by the
degree of sedation required and the susceptibility of the person to the main side events such as
extrapyramidal side effects (EPS). Second generation anti-psychotics (SGAs) such as risperidone,
quetiapine and olanzapine have less tendency to cause the same range of side effects as FGAs,
especially EPS which are more troublesome with FGAs.
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Clozapine is reserved for patients with schizophrenia who have not responded well to the use of two or
more antipsychotics (one of which should be an SGA) each for at least 6–8 weeks. Depot antipsychotics
(long acting injections) are used for maintenance therapy, usually for patients having difficulty taking with
oral medication (eg) forgetting to take, refusing to take. There are five FGA depot injections and two
By Eamonn Brady MPSI
SGAs (risperidone (Risperdal Consta®) and paliperidone (Xeplion®)) available in Ireland as a long-acting
injection.
Oral SGAs account for approximately 73% of antipsychotic medication prescribed. Advantages claimed
for these newer SGAs when they came out initially included better control of mood and less side effects.
However, experience and studies have since indicated that the perceived advantages of SGAs over FGAs
are not as strong as initially perceived in the early 1990s when SGAs first came out. Drug trials of second
generation antipsychotics initially conducted by manufacturers of SGAs have been heavily criticized for
being short-term and using participants not representative of patients encountered in actual practice.
However, SGAs appear to be more effective than older FGAs for negative symptoms of schizophrenia
(eg) poor motivation, lack of interest, poor self-care.
Schizophrenia
Premature mortality in people with schizophrenia exceeds that of the general population by about 50%.
This is due partly to a wide range of physical health problems; these include those induced by cigarette
smoking (which is more prevalent in schizophrenia patients than the general population), obesity and
diabetes. The tendency towards increased cardiovascular risk tends to be bought about by metabolic side
effects of antipsychotic medication including weight gain, high blood glucose levels and diabetes (brought
on by both FGAs and SGAs).
Two influential trials, CATIE and CUtLASS, indicated that the benefits of SGAs over FGAs (if any) were
not as significant as first thought. CUtLASS indicated there was no evidence that people prescribed FGAs
instead of SGAs would experience any disadvantage in relation to quality of life, symptoms or cost of
care. It was actually found that those prescribed FGAs did better in terms of overall symptom control and
level of side effects with the exception of clozapine. Another observation of the CUtLASS trial was the
clear superiority of clozapine in symptom improvement and patient preference. In fact, clozapine was
found to be twice as effective as the other SGAs in the CUtLASS trial. The risk of agranulocytosis (a
disorder of white blood cells) and the cost of blood tests is the main reason that clozapine is generally
reserved for when other medication fails which is estimated to be 30% of cases.
Studies show that 30% of schizophrenia patients have a relapse of symptoms during treatment with firstgeneration antipsychotic drugs compared with 80% without treatment.
Use of anti-psychotics for agitated behaviour in the elderly
In 2004 the Committee on Safety of Medicines in the UK first reported a clear increase in the risk of stroke
with the use of risperidone and olanzapine in elderly people with dementia. In 2005 a Europe-wide review
concluded that the risk could not be excluded for other SGAs or FGAs. 7 An extended follow up trial
called the dementia antipsychotic withdrawal trial (DART-AD) found that patients with Alzheimer’s
dementia who continued to use antipsychotics were more likely to die than those taking placebo (no
drug). Warnings from the European Medicines Agency and the Medicines and Healthcare products
Regulatory Authority reiterate the increased risk of stroke and a small increased risk of death when any
antipsychotics are used in elderly people with dementia. The NICE (UK health advisory body) guidance
on dementia advise that antipsychotics are only to be used in exceptional circumstances in such patients.
Disclaimer: Please ensure you consult with your healthcare professional before making any changes recommended
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