Antipsychotics, also known as neuroleptics, are a class of psychotropic medication primarily used to manage psychosis (including delusions, hallucinations, paranoia or disordered thought), principally in schizophrenia but also in a range of other psychotic disorders. They are also the mainstay together with mood stabilizers in the treatment of bipolar disorder.
Prior research has shown that use of any antipsychotic is associated with smaller brain tissue volumes, including white matter reduction and that this brain shrinkage is dose dependent and time dependent. A more recent controlled trial suggests that second generation antipsychotics combined with intensive psychosocial therapy may potentially prevent pallidal brain volume loss in first episode psychosis.
The use of antipsychotics may result in many unwanted side effects such as involuntary movement disorders, gynecomastia, impotence, weight gain and metabolic syndrome. Long-term use can produce adverse effects such as tardive dyskinesia, tardive dystonia, and tardive akathisia.
Prevention of these adverse effects is possible through
concomitant medication strategies including use of beta-blockers.
Currently, treatments for tardive diseases are not well established.
First-generation antipsychotics (e.g. chlorpromazine), known as typical antipsychotics, were first introduced in the 1950s, and others were developed until the early 1970s. Second-generation antipsychotics, known as atypical antipsychotics, were introduced firstly with clozapine in the early 1970s followed by others (e.g. risperidone). Both generations of medication block receptors in the brain for dopamine, but atypicals tend to act on serotonin receptors as well. Neuroleptic, originating from Greek: νεῦρον (neuron) and λαμβάνω (take hold of)—thus meaning "which takes the nerve"—refers to both common neurological effects and side effects.
Medical uses
Antipsychotics are most frequently used for the following conditions:
- Schizophrenia
- Schizoaffective disorder most commonly in conjunction with either an antidepressant (in the case of the depressive subtype) or a mood stabiliser (in the case of the bipolar subtype).
- Bipolar disorder
(acute mania and mixed episodes) may be treated with either typical or
atypical antipsychotics, although atypical antipsychotics are usually
preferred because they tend to have more favourable adverse effect
profiles and, according to a recent meta-analysis, they tend to have a lower liability for causing conversion from mania to depression.
- Psychotic depression.
In this indication it is a common practice for the psychiatrist to
prescribe a combination of an atypical antipsychotic and an
antidepressant as this practice is best supported by the evidence.
- Treatment resistant depression as an adjunct to standard antidepressant therapy.
Antipsychotics are generally not recommended for treating behavioral problems associated with dementia, given that the risk of use tends to be greater than the potential benefit. The same can be said for insomnia, in which they are not recommended as first-line therapy.
There are evidence-based indications for using antipsychotics in
children (e.g. tic disorder, bipolar disorder, psychosis), but the use
of antipsychotics outside of those contexts (e.g. to treat behavioral
problems) warrants significant caution.
Antipsychotics are used to treat tics associated with Tourette syndrome. Aripiprazole, an atypical antipsychotic, is used as add-on medication to ameliorate sexual dysfunction as a symptom of Selective serotonin reuptake inhibitor antidepressants in women. Quetiapine is used to treat generalized anxiety disorder.
Schizophrenia
Antipsychotic drug treatment is a key component of schizophrenia treatment recommendations by the National Institute of Health and Care Excellence (NICE), the American Psychiatric Association, and the British Society for Psychopharmacology. The main aim of treatment with antipsychotics is to reduce the positive symptoms of psychosis that include delusions and hallucinations. There is mixed evidence to support a significant impact of antipsychotic use on primary negative symptoms (such as apathy, lack of emotional affect, and lack of interest in social interactions) or on the cognitive symptoms (memory impairments, reduced ability to plan and execute tasks).
In general, the efficacy of antipsychotic treatment in reducing
positive symptoms appears to increase with increasing severity of
baseline symptoms.
All antipsychotic medications work relatively the same way, by
antagonizing D2 dopamine receptors. However, there are some differences
when it comes to typical and atypical antipsychotics. For example,
atypical antipsychotic medications have been seen to lower the
neurocognitive impairment associated with schizophrenia more so than
conventional antipsychotics, although the reasoning and mechanics of
this are still unclear to researchers.
Applications of antipsychotic drugs in the treatment of
schizophrenia include prophylaxis in those showing symptoms that suggest
that they are at high risk of developing psychosis, treatment of first
episode psychosis, maintenance therapy (a form of prophylaxis,
maintenance therapy aims to maintain therapeutic benefit and prevent
symptom relapse), and treatment of recurrent episodes of acute
psychosis.
Prevention of psychosis and symptom improvement
Test
batteries such as the PACE (Personal Assessment and Crisis Evaluation
Clinic) and COPS (Criteria of Prodromal Syndromes), which measure
low-level psychotic symptoms and cognitive disturbances, are used to
evaluate people with early, low-level symptoms of psychosis. Test
results are combined with family history information to identify
patients in the "high-risk" group; they are considered to have a 20–40%
risk of progression to frank psychosis within two years.
These patients are often treated with low doses of antipsychotic drugs
with the goal of reducing their symptoms and preventing progression to
frank psychosis. While generally useful for reducing symptoms, clinical
trials to date show little evidence that early use of antipsychotics
improves long-term outcomes in those with prodromal symptoms, either
alone or in combination with cognitive-behavioral therapy.
First episode psychosis
First
episode psychosis (FEP) is the first time that psychotic symptoms are
presented. NICE recommends that all persons presenting with first
episode psychosis be treated with both an antipsychotic drug, and cognitive behavioral therapy
(CBT). NICE further recommends that those expressing a preference for
CBT alone are informed that combination treatment is more effective. A diagnosis of schizophrenia is not made at this time as it takes longer to determine by both DSM-5 and ICD-11, and only around 60% of those presenting with a first episode psychosis will later be diagnosed with schizophrenia.
The conversion rate for a first episode drug induced psychosis to bipolar disorder or schizophrenia are lower, with 30% of people converting to either bipolar disorder or schizophrenia.
NICE makes no distinction between a substance-induced psychosis, and
any other form of psychosis. The rate of conversion differs for
different classes of drug.
Pharmacological options for the specific treatment of FEP have been discussed in recent reviews. The goals of treatment for FEP include reducing symptoms and
potentially improving long-term treatment outcomes. Randomized clinical
trials have provided evidence for the efficacy of antipsychotic drugs in
achieving the former goal, with first-generation and second generation
antipsychotics showing about equal efficacy. Evidence that early
treatment has a favorable effect on long term outcomes is equivocal.
Recurrent psychotic episodes
Placebo-controlled
trials of both first and second generation antipsychotic drugs
consistently demonstrate the superiority of active drug to placebo in
suppressing psychotic symptoms.
A large meta-analysis of 38 trials of antipsychotic drugs in
schizophrenia acute psychotic episodes showed an effect size of about
0.5.
There is little or no difference in efficacy among approved
antipsychotic drugs, including both first- and second-generation agents.
The efficacy of such drugs is suboptimal. Few patients achieve complete
resolution of symptoms. Response rates, calculated using various cutoff
values for symptom reduction, are low and their interpretation is
complicated by high placebo response rates and selective publication of
clinical trial results.
Maintenance therapy
The
majority of patients treated with an antipsychotic drug will experience
a response within four weeks. The goals of continuing treatment are to
maintain suppression of symptoms, prevent relapse, improve quality of
life, and support engagement in psychosocial therapy.
Maintenance therapy with antipsychotic drugs is clearly superior
to placebo in preventing relapse but is associated with weight gain,
movement disorders, and high dropout rates.
A 3-year trial following persons receiving maintenance therapy after an
acute psychotic episode found that 33% obtained long-lasting symptom
reduction, 13% achieved remission, and only 27% experienced satisfactory
quality of life. The effect of relapse prevention on long term outcomes
is uncertain, as historical studies show little difference in long term
outcomes before and after the introduction of antipsychotic drugs.
While maintenance therapy clearly reduces the rate of relapses
requiring hospitalization, a large observational study in Finland found
that, in people that eventually discontinued antipsychotics, the risk of
being hospitalized again for a mental health problem or dying increased
the longer they were dispensed (and presumably took) antipsychotics
prior to stopping therapy. If people did not stop taking antipsychotics,
they remained at low risk for relapse and hospitalization compared to
those that stopped taking antipsychotics.
The authors speculated that the difference may be because the people
that discontinued treatment after a longer time had more severe mental
illness than those that discontinued antipsychotic therapy sooner.
A significant challenge in the use of antipsychotic drugs for the prevention of relapse is the poor rate of adherence.
In spite of the relatively high rates of adverse effects associated
with these drugs, some evidence, including higher dropout rates in
placebo arms compared to treatment arms in randomized clinical trials,
suggest that most patients who discontinue treatment do so because of
suboptimal efficacy. If someone experiences psychotic symptoms due to nonadherence, they may be compelled to treatment through a process called involuntary commitment,
in which they can be forced to accept treatment (including
antipsychotics). A person can also be committed to treatment outside of a
hospital, called outpatient commitment.
Antipsychotics in long-acting injectable
(LAI), or "depot", form have been suggested as a method of decreasing
medication nonadherence (sometimes also called non-compliance). NICE advises LAIs be offered to patients when preventing covert, intentional nonadherence is a clinical priority. LAIs are used to ensure adherence in outpatient commitment.
A meta-analysis found that LAIs resulted in lower rates of
rehospitalization with a hazard ratio of 0.83, however these results
were not statistically significant (the 95% confidence interval was 0.62
to 1.11).
Bipolar disorder
Antipsychotics are routinely used, often in conjunction with mood stabilisers such as lithium/valproate, as a first-line treatment for manic and mixed episodes associated with bipolar disorder.
The reason for this combination is the therapeutic delay of the
aforementioned mood stabilisers (for valproate therapeutic effects are
usually seen around five days after treatment is commenced whereas
lithium usually takes at least a week before the full therapeutic effects are seen) and the comparatively rapid antimanic effects of antipsychotic drugs. The antipsychotics have a documented efficacy when used alone in acute mania/mixed episodes.
At least five atypical antipsychotics (lumateperone, cariprazine, lurasidone, olanzapine, and quetiapine) have also been found to possess efficacy in the treatment of bipolar depression as a monotherapy, whereas only olanzapine and quetiapine
have been proven to be effective broad-spectrum (i.e. against all three
types of relapse—manic, mixed and depressive) prophylactic (or maintenance)
treatments in patients with bipolar disorder. A recent Cochrane review
also found that olanzapine had a less favourable risk/benefit ratio than
lithium as a maintenance treatment for bipolar disorder.
The American Psychiatric Association and the UK National Institute for Health and Care Excellence
recommend antipsychotics for managing acute psychotic episodes in
schizophrenia or bipolar disorder, and as a longer-term maintenance
treatment for reducing the likelihood of further episodes.
They state that response to any given antipsychotic can be variable so
that trials may be necessary, and that lower doses are to be preferred
where possible. A number of studies have looked at levels of
"compliance" or "adherence" with antipsychotic regimes and found that
discontinuation (stopping taking them) by patients is associated with
higher rates of relapse, including hospitalization.
Dementia
Psychosis and agitation develop in as many as 80 percent of people living in nursing homes. Despite a lack of FDA approval and black-box warnings, atypical antipsychotics are very often prescribed to people with dementia. An assessment for an underlying cause of behavior is needed before prescribing antipsychotic medication for symptoms of dementia.
Antipsychotics in old age dementia showed a modest benefit compared to
placebo in managing aggression or psychosis, but this is combined with a
fairly large increase in serious adverse events. Thus, antipsychotics
should not be used routinely to treat dementia with aggression or
psychosis, but may be an option in a few cases where there is severe
distress or risk of physical harm to others. Psychosocial interventions may reduce the need for antipsychotics. In 2005, the FDA issued an advisory warning of an increased risk of death when atypical antipsychotics are used in dementia. In the subsequent 5 years, the use of atypical antipsychotics to treat dementia decreased by nearly 50%.
Major depressive disorder
A number of atypical antipsychotics have some benefits when used in addition to other treatments in major depressive disorder. Aripiprazole, quetiapine extended-release, and olanzapine (when used in conjunction with fluoxetine) have received the Food and Drug Administration (FDA) labelling for this indication. There is, however, a greater risk of side effects with their use compared to using traditional antidepressants.
The greater risk of serious side effects with antipsychotics is why,
e.g., quetiapine was denied approval as monotherapy for major depressive
disorder or generalized anxiety disorder, and instead was only approved
as an adjunctive treatment in combination with traditional
antidepressants.
Other
Besides the above uses antipsychotics may be used for obsessive–compulsive disorder, post-traumatic stress disorder, personality disorders, Tourette syndrome, autism and agitation in those with dementia. Evidence however does not support the use of atypical antipsychotics in eating disorders or personality disorder. The atypical antipsychotic risperidone may be useful for obsessive–compulsive disorder. The use of low doses of antipsychotics for insomnia, while common, is not recommended as there is little evidence of benefit as well as concern regarding adverse effects. Some of the more serious adverse effects may also occur at the low doses used, such as dyslipidemia and neutropenia,
and a recent network meta-analysis of 154 double-blind, randomized
controlled trials of drug therapies vs. placebo for insomnia in adults
found that quetiapine did not demonstrated any short-term benefits in
sleep quality. Low dose antipsychotics may also be used in treatment of impulse-behavioural and cognitive-perceptual symptoms of borderline personality disorder.
Despite the lack of evidence supporting the benefit of antipsychotics
in people with personality disorders, 1 in 4 who do not have a serious mental illness are prescribed them in UK primary care. Many people receive these medication for over a year, contrary to NICE guidelines.
In children they may be used in those with disruptive behavior disorders, mood disorders and pervasive developmental disorders or intellectual disability. Antipsychotics are only weakly recommended for Tourette syndrome, because although they are effective, side effects are common. The situation is similar for those on the autism spectrum.
Much of the evidence for the off-label use of antipsychotics (for
example, for dementia, OCD, PTSD, Personality Disorders, Tourette's) was
of insufficient scientific quality to support such use, especially as
there was strong evidence of increased risks of stroke, tremors,
significant weight gain, sedation, and gastrointestinal problems. A UK review of unlicensed usage in children and adolescents reported a similar mixture of findings and concerns. A survey of children with pervasive developmental disorder found that 16.5% were taking an antipsychotic drug, most commonly for irritability, aggression, and agitation. Both risperidone and aripiprazole have been approved by the US FDA for the treatment of irritability in autistic children and adolescents.
Aggressive challenging behavior in adults with intellectual disability is often treated with antipsychotic drugs despite lack of an evidence base. A recent randomized controlled trial, however, found no benefit over placebo and recommended that the use of antipsychotics in this way should no longer be regarded as an acceptable routine treatment.
Antipsychotics may be an option, together with stimulants, in
people with ADHD and aggressive behavior when other treatments have not
worked. They have not been found to be useful for the prevention of delirium among those admitted to hospital.
Typicals vs atypicals
It is unclear whether the atypical (second-generation) antipsychotics offer advantages over older, first generation antipsychotics. Amisulpride, olanzapine, risperidone and clozapine may be more effective but are associated with greater side effects. Typical antipsychotics have equal drop-out and symptom relapse rates to atypicals when used at low to moderate dosages.
Clozapine is an effective treatment for those who respond poorly
to other drugs ("treatment-resistant" or "refractory" schizophrenia), but it has the potentially serious side effect of agranulocytosis (lowered white blood cell count) in less than 4% of people.
Due to bias in the research the accuracy of comparisons of atypical antipsychotics is a concern.
In 2005, a US government body, the National Institute of Mental Health published the results of a major independent study (the CATIE project). No other atypical studied (risperidone, quetiapine, and ziprasidone)
did better than the typical perphenazine on the measures used, nor did
they produce fewer adverse effects than the typical antipsychotic
perphenazine, although more patients discontinued perphenazine owing to extrapyramidal effects compared to the atypical agents (8% vs. 2% to 4%).
Atypical antipsychotics do not appear to lead to improved rates of medication adherence compared to typical antipsychotics.
Many researchers question the first-line prescribing of atypicals
over typicals, and some even question the distinction between the two
classes. In contrast, other researchers point to the significantly higher risk of tardive dyskinesia
and other extrapyramidal symptoms with the typicals and for this reason
alone recommend first-line treatment with the atypicals,
notwithstanding a greater propensity for metabolic adverse effects in
the latter. The UK government organization NICE
recently revised its recommendation favoring atypicals, to advise that
the choice should be an individual one based on the particular profiles
of the individual drug and on the patient's preferences.
The re-evaluation of the evidence has not necessarily slowed the bias toward prescribing the atypicals.
Adverse effects
Generally, more than one antipsychotic drug should not be used at a time because of increased adverse effects.
Some atypicals are associated with considerable weight gain, diabetes and the risk of metabolic syndrome. Unwanted side effects cause people to stop treatment, resulting in relapses.
Risperidone (atypical) has a similar rate of extrapyramidal symptoms to haloperidol (typical). A rare but potentially lethal condition of neuroleptic malignant syndrome
(NMS) has been associated with the use of antipsychotics. Through its
early recognition, and timely intervention rates have declined. However,
an awareness of the syndrome is advised to enable intervention. Another less rare condition of tardive dyskinesia
can occur due to long-term use of antipsychotics, developing after
months or years of use. It is more often reported with use of typical
antipsychotics. Very rarely antipsychotics may cause tardive psychosis.
Clozapine is associated with side effects that include weight
gain, tiredness, and hypersalivation. More serious adverse effects
include seizures, NMS, neutropenia, and agranulocytosis (lowered white blood cell count) and its use needs careful monitoring.
Clozapine is also associated with thromboembolism (including pulmonary embolism), myocarditis, and cardiomyopathy.
A systematic review of clozapine-associated pulmonary embolism
indicates that this adverse effect can often be fatal, and that it has
an early onset, and is dose-dependent. The findings advised the
consideration of using a prevention therapy for venous thromboembolism after starting treatment with clozapine, and continuing this for six months. Constipation is three times more likely to occur with the use of clozapine, and severe cases can lead to ileus and bowel ischemia resulting in many fatalities.
Very rare clozapine adverse effects include periorbital edema due to
several possible mechanisms (e.g. inhibition of platelet-derived growth
factor receptors leading to increased vascular permeability, antagonism
of renal dopamine receptors with electrolyte and fluid imbalance and
immune-mediated hypersensitivity reactions).
However, the risk of serious adverse effects from clozapine is
low, and there are the beneficial effects to be gained of a reduced risk
of suicide, and aggression. Typical antipsychotics and atypical risperidone can have a side effect of sexual dysfunction.
Clozapine, olanzapine, and quetiapine are associated with beneficial
effects on sexual functioning helped by various psychotherapies.
By rate
Common (≥ 1% and up to 50% incidence for most antipsychotic drugs) adverse effects of antipsychotics include:
- Sedation (particularly common with asenapine, clozapine, olanzapine, quetiapine, chlorpromazine and zotepine)
- Headaches
- Dizziness
- Diarrhea
- Anxiety
- Extrapyramidal side effects (particularly common with first-generation antipsychotics), which include:
- - Akathisia, an often distressing sense of inner restlessness.
- - Dystonia, an abnormal muscle contraction
- - Pseudoparkinsonism, symptoms that are similar to what people with Parkinson's disease experience, including tremulousness and drooling
- Hyperprolactinaemia (rare for those treated with clozapine, quetiapine and aripiprazole), which can cause:
- - Galactorrhoea, the unusual secretion of breast milk.
- - Gynaecomastia, abnormal growth of breast tissue
- - Sexual dysfunction (in both sexes)
- - Osteoporosis
- Orthostatic hypotension
- Weight gain (particularly prominent with clozapine, olanzapine, quetiapine and zotepine)
- Anticholinergic side-effects (common for olanzapine, clozapine; less likely on risperidone) such as:
- - Blurred vision
- - Constipation
- - Dry mouth (although hypersalivation may also occur)
- - Reduced perspiration
- Tardive dyskinesia
appears to be more frequent with high-potency first-generation
antipsychotics, such as haloperidol, and tends to appear after chronic
and not acute treatment. It is characterized by slow (hence the tardive)
repetitive, involuntary and purposeless movements, most often of the
face, lips, legs, or torso, which tend to resist treatment and are
frequently irreversible. The rate of appearance of TD is about 5% per
year of use of antipsychotic drug (whatever the drug used)
- breast cancer:
a systematic review and meta-analysis of observational studies with
over 2 million individuals estimated an association between
antipsychotic use and breast cancer by over 30%.
Rare/Uncommon (<1% incidence for most antipsychotic drugs) adverse effects of antipsychotics include:
- Blood dyscrasias (e.g., agranulocytosis, leukopenia, and neutropaenia), which is more common in patients on clozapine.
- Metabolic syndrome and other metabolic problems such as type II diabetes mellitus — particularly common with clozapine, olanzapine and zotepine. In American studies African Americans appeared to be at a heightened risk for developing type II diabetes mellitus.
Evidence suggests that females are more sensitive to the metabolic side
effects of first-generation antipsychotic drugs than males. Metabolic adverse effects appear to be mediated by the following mechanisms:
- - Causing weight gain by antagonizing the histamine H1 and serotonin 5-HT2Creceptors and perhaps by interacting with other neurochemical pathways in the central nervous system.
- - Autonomic instability, which can manifest with tachycardia, nausea, vomiting, diaphoresis, etc.
- - Hyperthermia — elevated body temperature.
- - Mental status change (confusion, hallucinations, coma, etc.)
- - Muscle rigidity
- - Laboratory abnormalities (e.g., elevated creatine kinase, reduced iron plasma levels, electrolyte abnormalities, etc.)
Long-term effects
Some studies have found decreased life expectancy associated with the
use of antipsychotics, and argued that more studies are needed. Antipsychotics may also increase the risk of early death in individuals with dementia. Antipsychotics typically worsen symptoms in people with depersonalisation disorder. Antipsychotic polypharmacy
(prescribing two or more antipsychotics at the same time for an
individual) is a common practice but not evidence-based or recommended,
and there are initiatives to curtail it.
Similarly, the use of excessively high doses (often the result of
polypharmacy) continues despite clinical guidelines and evidence
indicating that it is usually no more effective but is usually more
harmful.
A meta-analysis of observational studies with over two million
individuals has suggested a moderate association of antipsychotic use
with breast cancer.
Loss of grey matter
and other brain structural changes over time are observed amongst
people diagnosed with schizophrenia. Meta-analyses of the effects of
antipsychotic treatment on grey matter volume and the brain's structure
have reached conflicting conclusions. A 2012 meta-analysis concluded
that grey matter loss is greater in patients treated with first
generation antipsychotics relative to those treated with atypicals, and
hypothesized a protective effect of atypicals as one possible
explanation. A second meta-analysis suggested that treatment with antipsychotics was associated with increased grey matter loss.
Animal studies found that monkeys exposed to both first- and
second-generation antipsychotics experience significant reduction in
brain volume, resulting in an 8-11% reduction in brain volume over a
17–27 month period.
The National Association of State Mental Health Program Directors
said that antipsychotics are not interchangeable and it is recommend
including trying at least one weight-neutral treatment for those
patients with potential metabolic issues.
Subtle, long-lasting forms of akathisia
are often overlooked or confused with post-psychotic depression, in
particular when they lack the extrapyramidal aspect that psychiatrists
have been taught to expect when looking for signs of akathisia.
Adverse effect on cognitive function and increased risk of death in people with dementia along with worsening of symptoms has been described in the literature.
Discontinuation
The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotics to avoid acute withdrawal syndrome or rapid relapse. Symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite. Other symptoms may include restlessness, increased sweating, and trouble sleeping. Less commonly there may be a feeling of the world spinning, numbness, or muscle pains. Symptoms generally resolve after a short period of time.
There is tentative evidence that discontinuation of antipsychotics can result in psychosis. It may also result in recurrence of the condition that is being treated. Rarely tardive dyskinesia can occur when the medication is stopped.
Unexpected psychotic episodes have been observed in patients withdrawing from clozapine. This is referred to as supersensitivity psychosis, not to be equated with tardive dyskinesia.
Tardive dyskinesia may abate during withdrawal from the antipsychotic agent, or it may persist.
Withdrawal effects may also occur when switching a person from
one antipsychotic to another, (it is presumed due to variations of
potency and receptor activity). Such withdrawal effects can include cholinergic rebound, an activation syndrome, and motor syndromes including dyskinesias.
These adverse effects are more likely during rapid changes between
antipsychotic agents, so making a gradual change between antipsychotics
minimises these withdrawal effects. The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotic treatment to avoid acute withdrawal syndrome or rapid relapse.
The process of cross-titration involves gradually increasing the dose
of the new medication while gradually decreasing the dose of the old
medication.
City and Hackney Clinical Commissioning Group
found more than 1,000 patients in their area in July 2019 who had not
had regular medication reviews or health checks because they were not
registered as having serious mental illness. On average they had been
taking these drugs for six years. If this is typical of practice in
England more than 100,000 patients are probably in the same position.
List of agents
Clinically used antipsychotic medications are listed below by drug
group. Trade names appear in parentheses. A 2013 review has stated that
the division of antipsychotics into first and second generation is
perhaps not accurate.
First-generation (typical)
Butyrophenones
Diphenylbutylpiperidines
Phenothiazines
Thioxanthenes
Disputed/unknown
This category is for drugs that have been called both first and second-generation, depending on the literature being used.
Benzamides
Tricyclics
Others
Second-generation (atypical)
Benzamides
- Amisulpride ‡
– Selective dopamine antagonist. Higher doses (greater than 400 mg) act
upon post-synaptic dopamine receptors resulting in a reduction in the
positive symptoms of schizophrenia, such as psychosis. Lower doses,
however, act upon dopamine autoreceptors, resulting in increased
dopamine transmission, improving the negative symptoms of schizophrenia.
Lower doses of amisulpride have also been shown to have antidepressant and anxiolytic effects in non-schizophrenic patients, leading to its use in dysthymia and social phobias.
- Nemonapride † – Used in Japan.
- Remoxipride # – Has a risk of causing aplastic anaemia
and, hence, has been withdrawn from the market worldwide. It has also
been found to possess relatively low (virtually absent) potential to
induce hyperprolactinaemia and extrapyramidal symptoms, likely attributable to its comparatively weak binding to (and, hence, rapid dissociation from) the D2 receptor.
- Sultopride
– An atypical antipsychotic of the benzamide chemical class used in
Europe, Japan, and Hong Kong for the treatment of schizophrenia. It was
launched by Sanofi-Aventis in 1976. Sultopride acts as a selective D2
and D3 receptor antagonist.
Benzisoxazoles/benzisothiazoles
- Lumateperone – In December 2019, lumateperone received its first global approval in the USA for the treatment of schizophrenia in adults.
In 2020 and 2021 FDA approved for depressive episodes associated with
bipolar I or II disorder (bipolar depression) in adults, as monotherapy
and as adjunctive therapy with lithium or valproate.
- Iloperidone – Approved by the US FDA in 2009, it is fairly well tolerated, although hypotension, dizziness, and somnolence were very common side effects. Has not received regulatory approval in other countries, however.
- Paliperidone – Primary, active metabolite of risperidone that was approved in 2006.
- Perospirone † – Has a higher incidence of extrapyramidal side effects than other atypical antipsychotics.
- Risperidone
– Divided dosing is recommended until initial titration is completed,
at which time the drug can be administered once daily. Used off-label to
treat Tourette syndrome and anxiety disorder.
- Ziprasidone – Approved in 2004 to treat bipolar disorder. Side-effects include a prolonged QT interval in the heart, which can be dangerous for patients with heart disease or those taking other drugs that prolong the QT interval.
- Lurasidone – Approved by the US FDA for schizophrenia and bipolar depression, and for use as schizophrenia treatment in Canada.
Butyrophenones
- Melperone † – Only used in a few European countries. No English-speaking country has licensed it to date.
- Lumateperone
Tricyclics
- Asenapine – Used for the treatment of schizophrenia and acute mania associated with bipolar disorder.
- Clozapine – Requires routine laboratory monitoring of complete blood counts every one to four weeks due to the risk of agranulocytosis. It has unparalleled efficacy in the treatment of treatment-resistant schizophrenia.
- Olanzapine – Used to treat psychotic disorders including schizophrenia, acute manic episodes, and maintenance of bipolar disorder. Used as an adjunct to antidepressant therapy, either alone or in combination with fluoxetine as Symbyax.
- Quetiapine
– Used primarily to treat bipolar disorder and schizophrenia. Also used
and licensed in a few countries (including Australia, the United
Kingdom and the United States) as an adjunct to antidepressant therapy
in patients with major depressive disorder. It's the only antipsychotic that's demonstrated efficacy as a monotherapy for the treatment of major depressive disorder. It indirectly serves as a norepinephrine reuptake inhibitor by means of its active metabolite, norquetiapine.
- Zotepine
– An atypical antipsychotic indicated for acute and chronic
schizophrenia. It is still used in Japan and was once used in Germany
but it was discontinued.†
Others
- Blonanserin – Approved by the PMDA in 2008. Used in Japan and South Korea.
- Pimavanserin – A selective 5-HT2A receptor antagonist approved for the treatment of Parkinson's disease psychosis in 2016.
- Sertindole ‡ – Developed by the Danish pharmaceutical company H. Lundbeck. Like the other atypical antipsychotics, it is believed to have antagonist activity at dopamine and serotonin receptors in the brain.
Third-generation
Third generation antipsychotics are recognized as demonstrating D2 receptor agonism as opposed to the D2 receptor antagonistic mechanism of both first-generation (typical) and second-generation (atypical) antipsychotic medications.
Phenylpiperazines/quinolinones
- Aripiprazole (Abilify) – Partial agonist at the D2 receptor. Considered the prototypical third-generation antipsychotic.
- Aripiprazole lauroxil (Abilify Maintena)– Long-acting version of aripiprazole for injection.
- Brexpiprazole – Partial agonist of the D2 receptor. Successor of aripiprazole.
- Cariprazine – A D3-preferring D2/D3 partial agonist.
Mechanism of action
Antipsychotic drugs such as haloperidol and chlorpromazine tend to block dopamine D2 receptors in the dopaminergic pathways of the brain. This means that dopamine released in these pathways has less effect. Excess release of dopamine in the mesolimbic pathway
has been linked to psychotic experiences. Decreased dopamine release in
the prefrontal cortex, and excess dopamine release in other pathways,
are associated with psychotic episodes in schizophrenia and bipolar
disorder.
In addition to the antagonistic effects of dopamine, antipsychotics (in particular atypical neuroleptics) also antagonize 5-HT2A receptors. Different alleles of the 5-HT2A receptor have been associated with schizophrenia and other psychoses, including depression. Higher concentrations of 5-HT2A receptors in cortical and subcortical areas, in particular in the right caudate nucleus have been historically recorded.
Typical antipsychotics are not particularly selective and also block dopamine receptors in the mesocortical pathway, tuberoinfundibular pathway, and the nigrostriatal pathway. Blocking D2 receptors in these other pathways is thought to produce some unwanted side effects
that the typical antipsychotics can produce (see above). They were
commonly classified on a spectrum of low potency to high potency, where
potency referred to the ability of the drug to bind to dopamine
receptors, and not to the effectiveness of the drug. High-potency
antipsychotics such as haloperidol,
in general, have doses of a few milligrams and cause less sleepiness
and calming effects than low-potency antipsychotics such as chlorpromazine and thioridazine,
which have dosages of several hundred milligrams. The latter have a
greater degree of anticholinergic and antihistaminergic activity, which
can counteract dopamine-related side-effects.
Atypical antipsychotic drugs have a similar blocking effect on D2 receptors; however, most also act on serotonin receptors, especially 5-HT2A and 5-HT2C
receptors. Both clozapine and quetiapine appear to bind just long
enough to elicit antipsychotic effects but not long enough to induce
extrapyramidal side effects and prolactin hypersecretion. 5-HT2A antagonism increases dopaminergic activity in the nigrostriatal pathway, leading to a lowered extrapyramidal side effect liability among the atypical antipsychotics.
Comparison of medications
History
Advertisement for Thorazine (
chlorpromazine)
from the 1950s, reflecting the perceptions of psychosis, including the
now-discredited perception of a tendency towards violence, from the time
when antipsychotics were discovered
The original antipsychotic drugs were happened upon largely by chance and then tested for their effectiveness. The first, chlorpromazine, was developed as a surgical anesthetic.
It was first used on psychiatric patients because of its powerful
calming effect; at the time it was regarded as a non-permanent
"pharmacological lobotomy".
Lobotomy at the time was used to treat many behavioral disorders,
including psychosis, although its effect was to markedly reduce behavior
and mental functioning of all types. However, chlorpromazine proved to
reduce the effects of psychosis in a more effective and specific manner
than lobotomy, even though it was known to be capable of causing severe
sedation. The underlying neurochemistry involved has since been studied in detail, and subsequent antipsychotic drugs have been developed by rational drug design.
The discovery of chlorpromazine's psychoactive effects in 1952 led to further research that resulted in the development of antidepressants, anxiolytics, and the majority of other drugs now used in the management of psychiatric conditions. In 1952, Henri Laborit
described chlorpromazine only as inducing indifference towards what was
happening around them in nonpsychotic, nonmanic patients, and Jean Delay and Pierre Deniker
described it as controlling manic or psychotic agitation. The former
claimed to have discovered a treatment for agitation in anyone, and the
latter team claimed to have discovered a treatment for psychotic
illness.
Until the 1970s there was considerable debate within psychiatry on the most appropriate term to use to describe the new drugs. In the late 1950s the most widely used term was "neuroleptic", followed by "major tranquilizer" and then "ataraxic". The first recorded use of the term tranquilizer dates from the early nineteenth century. In 1953 Frederik F. Yonkman, a chemist at the Swiss-based Cibapharmaceutical company, first used the term tranquilizer to differentiate reserpine from the older sedatives. The word neuroleptic was coined in 1955 by Delay and Deniker after their discovery (1952) of the antipsychotic effects of chlorpromazine. It is derived from the Greek: "νεῦρον" (neuron, originally meaning "sinew" but today referring to the nerves) and "λαμβάνω" (lambanō, meaning "take hold of"). Thus, the word means taking hold of one's nerves.
It was often taken to refer also to common side effects such as reduced
activity in general, as well as lethargy and impaired motor control.
Although these effects are unpleasant and in some cases harmful, they
were at one time, along with akathisia, considered a reliable sign that
the drug was working.
The term "ataraxy" was coined by the neurologist Howard Fabing and the
classicist Alister Cameron to describe the observed effect of psychic
indifference and detachment in patients treated with chlorpromazine. This term derived from the Greek adjective "ἀτάρακτος" (ataraktos), which means "not disturbed, not excited, without confusion, steady, calm".
In the use of the terms "tranquilizer" and "ataractic", medical
practitioners distinguished between the "major tranquilizers" or "major
ataractics", which referred to drugs used to treat psychoses, and the
"minor tranquilizers" or "minor ataractics", which referred to drugs
used to treat neuroses.
While popular during the 1950s, these terms are infrequently used
today. They are being abandoned in favor of "antipsychotic", which
refers to the drug's desired effects. Today, "minor tranquilizer" can refer to anxiolytic and/or hypnotic drugs such as the benzodiazepines and nonbenzodiazepines, which are useful as generally short-term management for insomnia together with cognitive behavioral therapy for insomnia. They are potentially addictive sedatives.
Antipsychotics are broadly divided into two groups, the typical or first-generation antipsychotics and the atypical or second-generation antipsychotics.
The difference between first- and second-generation antipsychotics is a
subject of debate. The second-generation antipsychotics are generally
distinguishable by the presence of 5HT2A receptor antagonism and a corresponding lower propensity for extrapyramidal side effects compared to first-generation antipsychotics.
Society and culture
Terminology
The term major tranquilizer was used for older antipsychotic drugs. The term neuroleptic is often used as a synonym for antipsychotic, even though – strictly speaking – the two terms are not interchangeable. Antipsychotic drugs are a subgroup of neuroleptic drugs, because the latter have a wider range of effects.
Antipsychotics are a type of psychoactive or psychotropic medication.
Sales
Antipsychotics
were once among the biggest selling and most profitable of all drugs,
generating $22 billion in global sales in 2008.
By 2003 in the US, an estimated 3.21 million patients received
antipsychotics, worth an estimated $2.82 billion. Over 2/3 of
prescriptions were for the newer, more expensive atypicals, each costing
on average $164 per year, compared to $40 for the older types. By 2008, sales in the US reached $14.6 billion, the biggest selling drugs in the US by therapeutic class.
In the five years since July 2017 the number of antipsychotic
medicines dispensed in the community in the United Kingdom has increased
by 11.2%. There have also been substantial price rises. Risperidone
6 mg tablets, the largest, increased from £3.09 in July 2017 to £41.16
in June 2022. The NHS
is spending an additional £33 million annually on antipsychotics.
Haloperidol 500 microgram tablets constituted £14.3 million of this.
Overprescription
Antipsychotics
in the nursing home population are often overprescribed, often for the
purposes of making it easier to handle dementia patients. Federal
efforts to reduce the use of antipsychotics in US nursing homes has led
to a nationwide decrease in their usage in 2012.
Legal
Antipsychotics are sometimes administered as part of compulsory psychiatric treatment via inpatient (hospital) commitment or outpatient commitment.
Formulations
They may be administered orally or, in some cases, through long-acting (depot) injections administered in the dorsgluteal, ventrogluteal or deltoid muscle.
Short-acting parenteral formulations also exist, which are generally
reserved for emergencies or when oral administration is otherwise
impossible. The oral formulations include immediate release, extended
release, and orally disintegrating products (which are not sublingual,
and can help ensure that medications are swallowed instead of
"cheeked"). Sublingual products (e.g. asenapine) also exist, which must be held under the tongue for absorption. The first transdermal formulation of an antipsychotic (transdermal asenapine, marketed as Secuado), was FDA-approved in 2019.
Recreational use
Certain second-generation antipsychotics are misused or abused for their sedative, tranquilizing, and (paradoxically) "hallucinogenic" effects. The most commonly second-generation antipsychotic implicated is quetiapine.
In case reports, quetiapine has been abused in doses taken by mouth
(which is how the drug is available from the manufacturer), but also
crushed and insufflated or mixed with water for injection into a vein. Olanzapine, another sedating second-generation antipsychotic, has also been misused for similar reasons.
There is no standard treatment for antipsychotic abuse, though
switching to a second-generation antipsychotic with less abuse potential
(e.g. aripiprazole) has been used.
Controversy
Joanna Moncrieff
has argued that antipsychotic drug treatment is often undertaken as a
means of control rather than to treat specific symptoms experienced by
the patient.
Use of this class of drugs has a history of criticism in
residential care. As the drugs used can make patients calmer and more
compliant, critics claim that the drugs can be overused. Outside doctors
can feel under pressure from care home staff.
In an official review commissioned by UK government ministers it was
reported that the needless use of antipsychotic medication in dementia
care was widespread and was linked to 1800 deaths per year. In the US, the government has initiated legal action against the pharmaceutical company Johnson & Johnson for allegedly paying kickbacks to Omnicare to promote its antipsychotic risperidone (Risperdal) in nursing homes.
There has also been controversy about the role of pharmaceutical companies in marketing
and promoting antipsychotics, including allegations of downplaying or
covering up adverse effects, expanding the number of conditions or
illegally promoting off-label usage; influencing drug trials (or their
publication) to try to show that the expensive and profitable newer
atypicals were superior to the older cheaper typicals that were out of
patent. Following charges of illegal marketing, settlements by two large
pharmaceutical companies in the US set records for the largest criminal
fines ever imposed on corporations. One case involved Eli Lilly and Company's antipsychotic Zyprexa, and the other involved Bextra. In the Bextra case, the government also charged Pfizer with illegally marketing another antipsychotic, Geodon. In addition, AstraZeneca faces numerous personal-injury lawsuits from former users of Seroquel (quetiapine), amidst federal investigations of its marketing practices.
By expanding the conditions for which they were indicated,
Astrazeneca's Seroquel and Eli Lilly's Zyprexa had become the biggest
selling antipsychotics in 2008 with global sales of $5.5 billion and
$5.4 billion respectively.
Harvard University medical professor Joseph Biederman conducted research on bipolar disorder in children that led to an increase in such diagnoses. A 2008 Senate
investigation found that Biederman also received $1.6 million in
speaking and consulting fees between 2000 and 2007, some of them
undisclosed to Harvard, from companies including makers of antipsychotic
drugs prescribed for children with bipolar disorder. Johnson & Johnson
gave more than $700,000 to a research center that was headed by
Biederman from 2002 to 2005, where research was conducted, in part, on Risperdal,
the company's antipsychotic drug. Biederman has responded saying that
the money did not influence him and that he did not promote a specific
diagnosis or treatment.
Pharmaceutical companies have also be
en accused of attempting to
set the mental health agenda through activities such as funding consumer advocacy groups.
Special populations
It
is recommended that persons with dementia who exhibit behavioral and
psychological symptoms should not be given antipsychotics before trying
other treatments. When taking antipsychotics this population has increased risk of cerebrovascular effects, parkinsonism or extrapyramidal symptoms, sedation, confusion and other cognitive adverse effects, weight gain, and increased mortality.
Physicians and caretakers of persons with dementia should try to
address symptoms including agitation, aggression, apathy, anxiety,
depression, irritability, and psychosis with alternative treatments
whenever antipsychotic use can be replaced or reduced. Elderly persons often have their dementia treated first with antipsychotics and this is not the best management strategy.
