Antipsychotic

Antipsychotics, previously known as neuroleptics^[1] and major tranquilizers,^[2] 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.^[3][4] They are also the mainstay, together with mood stabilizers, in the treatment of bipolar disorder.^[5] Moreover, they are also used as adjuncts in the treatment of treatment-resistant major depressive disorder.

Antipsychotic
Drug class
Olanzapine, an example of a second-generation (atypical) antipsychotic
Class identifiers
Synonyms	Neuroleptics, major tranquilizers^[1]
Use	Principally: Schizophrenia, Schizoaffective disorder, Dementia, Tourette syndrome, Bipolar disorder, irritability in autism spectrum disorder
Clinical data
Drugs.com	Drug Classes
External links
MeSH	D014150
Legal status
In Wikidata

While some research has shown that use of any antipsychotic is associated with smaller brain tissue volumes,^[6][7] including white matter reduction^[8] and that this reduction is dose dependent and time dependent,^[6][7] schizophrenia is itself a neurodegenerative disorder associated with reduced brain tissue volumes.^[9] A more recent controlled trial suggests that second generation antipsychotics^[10] combined with intensive psychosocial therapy^[11] may potentially prevent pallidal brain volume loss in first episode psychosis.^[12][8]

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 syndromes include VMAT2 inhibitors.

First-generation antipsychotics (e.g., chlorpromazine), known as typical antipsychotics, were first introduced in the 1950s, and others were developed until the early 1970s.^[13] Second-generation antipsychotics, known as atypical antipsychotics, arrived with the introduction of clozapine in the early 1970s followed by others (e.g., risperidone).^[14] Both generations of medication block receptors in the brain for dopamine, but atypicals block serotonin receptors as well. Third-generation antipsychotics were introduced in the 2000s and offer partial agonism, rather than blockade, of dopamine receptors.^[15] 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.^[16]

Medical uses

Antipsychotics are most frequently used for the following conditions:

• Schizophrenia^[3]
• 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). Antipsychotics possess mood stabilizing properties and thus they may be used as standalone medication to treat mood dysregulation.
• 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^[17] and, according to a recent meta-analysis, they tend to have a lower liability for causing conversion from mania to depression.^[18]
• 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.^[19]
• Treatment resistant depression as an adjunct to standard antidepressant therapy.^[19]

Given the limited options available to treat the behavioral problems associated with dementia, other pharmacological and non-pharmacological interventions are usually attempted before using antipsychotics. A risk-to-benefit analysis is performed to weigh the risk of the adverse effects of antipsychotics versus: the potential benefit, the adverse effects of alternative interventions, and the risk of failing to intervene when a patient's behavior becomes unsafe.^[20] The same can be said for insomnia, in which they are not recommended as first-line therapy.^[20] 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.^[20]

Antipsychotics are used to treat tics associated with Tourette syndrome.^[21] 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.^[22]: 10 Quetiapine is used to treat generalized anxiety disorder.^[23]

Schizophrenia

Main article: Schizophrenia § Medication

Antipsychotic drug treatment is a key component of schizophrenia treatment recommendations by the National Institute of Health and Care Excellence (NICE),^[24] the American Psychiatric Association,^[25] and the British Society for Psychopharmacology.^[26] The main aim of treatment with antipsychotics is to reduce the positive symptoms of psychosis, that include delusions and hallucinations.^[3] 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 cognitive symptoms (memory impairments, reduced ability to plan and execute tasks).^[27][28] In general, the efficacy of antipsychotic treatment in reducing positive symptoms appears to increase with the severity of baseline symptoms.^[29] 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 than conventional antipsychotics, although the reasoning and mechanics of this are still unclear to researchers.^[30]

Applications of antipsychotic drugs in the treatment of schizophrenia include prophylaxis for 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.^[3][26]

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.^[26] 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.^[31]

First-episode psychosis

First-episode psychosis (FEP) is the first time that psychotic symptoms are presented. NICE recommends that all people 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 be informed that combination treatment is more effective.^[24] A diagnosis of schizophrenia is not made at this time as it takes longer to be determined by both DSM-5 and ICD-11, and only around 60% of those presenting with a first episode of psychosis will later be diagnosed with schizophrenia.^[32]

The conversion rate for a first episode of drug induced psychosis to bipolar disorder or schizophrenia is lower, with 30% of people converting to either bipolar disorder or schizophrenia.^[33] NICE makes no distinction between substance-induced psychosis and any other form of psychosis. The rate of conversion differs for different classes of drugs.^[33]

Pharmacological options for the specific treatment of FEP have been discussed in recent reviews.^[34][35] 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. The evidence that early treatment has a favorable effect on long-term outcomes is equivocal.^[24][26]

Recurrent psychotic episodes

Placebo-controlled trials of both first- and second-generation antipsychotic drugs consistently demonstrate the superiority of active drugs over placebos in suppressing psychotic symptoms.^[26] A large meta-analysis of 38 trials of antipsychotic drugs in schizophrenia with acute psychotic episodes showed an effect size of about 0.5.^[36] There is little or no difference in efficacy among approved antipsychotic drugs, including both first- and second-generation agents.^[24][37] 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.^[38]

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.^[3][26]

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.^[39] 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.^[26]

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 did.^[40] 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.^[40]

A significant challenge in the use of antipsychotic drugs for the prevention of relapse is the poor rate of adherence.^[3] 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, suggests that most patients who discontinue treatment do so because of suboptimal efficacy.^[39][41] If someone experiences psychotic symptoms due to nonadherence, they may be compelled to receive 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).^[3][42] NICE advises LAIs be offered to patients when preventing covert, intentional nonadherence is a clinical priority.^[43] LAIs are used to ensure adherence in outpatient commitment.^[3][44] 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).^[42]

Bipolar disorder

Main article: 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.^[19][45] 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^[45] before the full therapeutic effects are seen) and the comparatively rapid antimanic effects of antipsychotic drugs.^[46] The antipsychotics have a documented efficacy when used alone in acute mania/mixed episodes.^[17]

At least five atypical antipsychotics (lumateperone,^[47] cariprazine,^[48] lurasidone,^[49] olanzapine,^[50] and quetiapine^[51]) have also been found to possess efficacy in the treatment of bipolar depression as a monotherapy, whereas only olanzapine^[52] and quetiapine^[53][54] 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.^[55]

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.^[56][57] 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.^[58] Despite a lack of FDA approval and black-box warnings, atypical antipsychotics are very often prescribed to people with dementia.^[58] An assessment for an underlying cause of behavior is needed before prescribing antipsychotic medication for symptoms of dementia.^[59] 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.^[60] Psychosocial interventions may reduce the need for antipsychotics.^[61] In 2005, the FDA issued an advisory warning of an increased risk of death when atypical antipsychotics are used in dementia.^[58] In the subsequent 5 years, the use of atypical antipsychotics to treat dementia decreased by nearly 50%.^[58]

Major depressive disorder

A number of atypical antipsychotics have some benefits when used in addition to other treatments in major depressive disorder.^[62][63] Aripiprazole, quetiapine extended-release, and olanzapine (when used in conjunction with fluoxetine) have received the Food and Drug Administration (FDA) labelling for this indication.^[64] There is, however, a greater risk of side effects with their use compared to using traditional antidepressants.^[62] 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.^[65]

A recent study on the use of antipychotics in unipolar depression concluded that the use of those drugs in addition to antidepressants alone leads to a worse disease outcome. This effect is especially pronounced in younger patients with psychotic unipolar depression. Considering the wide use of such combination therapies, further studies on the side effects of antipychotics as an add-on therapy are warranted.^[66]

Other

Global antipsychotic utilization has seen a steady growth since the introduction of atypical (second-generation) antipsychotics and this is ascribed to off-label use for many other unapproved disorders.^[67][68][69] 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.^[70] Evidence however does not support the use of atypical antipsychotics in eating disorders or personality disorder.^[71] The atypical antipsychotic risperidone may be useful for obsessive–compulsive disorder.^[70] 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.^[71][72] Some of the more serious adverse effects may also occur at the low doses used, such as dyslipidemia and neutropenia,^[73][74] 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.^[75] Low dose antipsychotics may also be used in treatment of impulse-behavioural and cognitive-perceptual symptoms of borderline personality disorder.^[76] 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.^[77][78]

In children they may be used in those with disruptive behavior disorders, mood disorders and pervasive developmental disorders or intellectual disability.^[79] Antipsychotics are only weakly recommended for Tourette syndrome, because although they are effective, side effects are common.^[80] The situation is similar for those on the autism spectrum.^[81] 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.^[82] A UK review of unlicensed usage in children and adolescents reported a similar mixture of findings and concerns.^[83] 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.^[84] A review in the UK found that the use of antipsychotics in England doubled between 2000 and 2019. Children were prescribed antipsychotics for conditions for which there is no approval, such as autism.^[85][86]

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.^[87]

Antipsychotics may be an option, together with stimulants, in people with ADHD and aggressive behavior when other treatments have not worked.^[88] They have not been found to be useful for the prevention of delirium among those admitted to hospital.^[89]

Typicals vs atypicals

Aside from reduced extrapyramidal symptoms, and with the clear exception of clozapine, it is unclear whether the atypical (second-generation) antipsychotics offer advantages over older, first generation antipsychotics.^[3][28][90] Amisulpride, olanzapine, risperidone and clozapine may be more effective but are associated with greater side effects.^[91] Typical antipsychotics have equal drop-out and symptom relapse rates to atypicals when used at low to moderate dosages.^[92]

Clozapine is an effective treatment for those who respond poorly to other drugs ("treatment-resistant" or "refractory" schizophrenia),^[93] but it has the potentially serious side effect of agranulocytosis (lowered white blood cell count) in less than 4% of people.^[94]

Due to bias in the research the accuracy of comparisons of atypical antipsychotics is a concern.^[95]

In 2005, a US government body, the National Institute of Mental Health published the results of a major independent study (the CATIE project).^[96] No other atypical studied (risperidone, quetiapine, and ziprasidone) did better than the first-generation antipsychotic 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%).^[17] This is significant because any patient with tardive dyskinesia was specifically excluded from randomization to perphenazine; i.e., in the CATIE study the patient cohort randomized to receive perphenazne was at lower risk of having extrapyramidal symptoms.^[97]

Atypical antipsychotics do not appear to lead to improved rates of medication adherence compared to typical antipsychotics.^[98]

Many researchers question the first-line prescribing of atypicals over typicals, and some even question the distinction between the two classes.^{[99][100][101]} 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.^[102] 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.^[103]

Adverse effects

For more detailed comparison of atypical antipsychotics, see Atypical antipsychotic § Adverse effects.

Generally, more than one antipsychotic drug should not be used at a time because of increased adverse effects.^[104]

Some atypicals are associated with considerable weight gain, diabetes and the risk of metabolic syndrome.^[105] Unwanted side effects cause people to stop treatment, resulting in relapses.^[106] Risperidone (atypical) has a similar rate of extrapyramidal symptoms to haloperidol (typical).^[105] 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.^[107] 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.^[108] Very rarely antipsychotics may cause tardive psychosis.^[109]

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.^[110][111]

Clozapine is also associated with thromboembolism (including pulmonary embolism), myocarditis, and cardiomyopathy.^[112][113] 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.^[113] 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.^[110] 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).^[114]

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.^[115][116] Typical antipsychotics and atypical risperidone can have a side effect of sexual dysfunction.^[117] Clozapine, olanzapine, and quetiapine are associated with beneficial effects on sexual functioning helped by various psychotherapies.^[118]

By rate

Common (≥ 1% and up to 50% incidence for most antipsychotic drugs) adverse effects of antipsychotics include:^[119]

• Dysphoria and apathy (due to dopamine receptor blockade)
• Sedation (particularly common with asenapine, clozapine, olanzapine, quetiapine, chlorpromazine and zotepine^[37])
• 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^[19][37]), 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^[37])
• Anticholinergic side-effects (common for olanzapine, clozapine; less likely on risperidone^[120]) 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%.^[121]

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.^[122] Evidence suggests that females are more sensitive to the metabolic side effects of first-generation antipsychotic drugs than males.^[123] Metabolic adverse effects appear to be mediated by the following mechanisms:

- Causing weight gain by antagonizing the histamine H₁ and serotonin 5-HT_2C receptors^[124] and perhaps by interacting with other neurochemical pathways in the central nervous system.^[125]

• Neuroleptic malignant syndrome, a potentially fatal condition characterized by:

- 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.)

• Pancreatitis^[126]
• QT interval prolongation — more prominent in those treated with amisulpride, pimozide, sertindole, thioridazine and ziprasidone.^[19][37]
• Torsades de pointes
• Seizures, particularly in people treated with chlorpromazine and clozapine.
• Thromboembolism
• Myocardial infarction
• Stroke
• Pisa syndrome

Long-term effects

See also: List of long term side effects of antipsychotics

Some studies have found decreased life expectancy associated with the use of antipsychotics, and argued that more studies are needed.^[127][128] Antipsychotics may also increase the risk of early death in individuals with dementia.^[129] Antipsychotics typically worsen symptoms in people with depersonalisation disorder.^[130] 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.^[104][131] 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.^[104][132] A meta-analysis of observational studies with over two million individuals has suggested a moderate association of antipsychotic use with breast cancer.^[133]

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.^[134] A second meta-analysis suggested that treatment with antipsychotics was associated with increased grey matter loss.^[135] 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.^[136]

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.^[137]

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.^[138]

Adverse effect on cognitive function^{[139][140][141]} and increased risk of death in people with dementia along with worsening of symptoms has been described in the literature.^[142][143]

Discontinuation

See also: Drug withdrawal § Prescription medicine

The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotics to avoid acute withdrawal syndrome or rapid relapse.^[144] Symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite.^[145] Other symptoms may include restlessness, increased sweating, and trouble sleeping.^[145] Less commonly there may be a feeling of the world spinning, numbness, or muscle pains.^[145] Symptoms generally resolve after a short period of time.^[145]

There is tentative evidence that discontinuation of antipsychotics can result in psychosis.^[146] It may also result in recurrence of the condition that is being treated.^[147] Rarely tardive dyskinesia can occur when the medication is stopped.^[145]

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.^[146][148]

Tardive dyskinesia may abate during withdrawal from the antipsychotic agent, or it may persist.^[149]

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.^[150] The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotic treatment to avoid acute withdrawal syndrome or rapid relapse.^[151] 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.^[152]

List of agents

 

Chlorpromazine

 

Haloperidol

 

Quetiapine

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.^[37]

Notes:

† indicates drugs that are no longer (or were never) marketed in English-speaking countries.

‡ denotes drugs that are no longer (or were never to begin with) marketed in the United States. Some antipsychotics are not firmly placed in either first-generation or second-generation classes.

# denotes drugs that have been withdrawn worldwide.

First-generation (typical)

Main article: Typical antipsychotic

Butyrophenones

Main article: Butyrophenones

• Benperidol^‡
• Bromperidol^†
• Droperidol^‡
• Haloperidol (Haldol)
• Moperone (discontinued)^†
• Pipamperone (discontinued)^†
• Timiperone ^†

Diphenylbutylpiperidines

• Fluspirilene ‡
• Penfluridol ‡
• Pimozide

Phenothiazines

Main article: Phenothiazines

• Acepromazine ^† — although it is mostly used in veterinary medicine.
• Chlorpromazine (Thorazine)
• Cyamemazine ^†
• Dixyrazine ^†
• Fluphenazine
• Levomepromazine^‡
• Mesoridazine (discontinued)^†
• Perazine
• Pericyazine^‡
• Perphenazine
• Pipotiazine ^‡
• Prochlorperazine
• Promazine (discontinued)
• Promethazine
• Prothipendyl ^†
• Thioproperazine^‡ (only English-speaking country it is available in is Canada)
• Thioridazine (discontinued)
• Trifluoperazine
• Triflupromazine (discontinued)^†

Thioxanthenes

Main article: Thioxanthenes

• Chlorprothixene ^†
• Clopenthixol
• Flupentixol ^‡
• Thiothixene
• Zuclopenthixol ^‡

Disputed/unknown

This category is for drugs that have been called both first and second-generation, depending on the literature being used.

Benzamides

• Sulpiride ^‡
• Sultopride ^†
• Veralipride ^†

Tricyclics

• Carpipramine ^†
• Clocapramine ^†
• Clorotepine ^†
• Clotiapine ^‡
• Loxapine
• Mosapramine ^†

Others

• Molindone ^#

Second-generation (atypical)

Main article: Atypical antipsychotic

Benzamides

• Amisulpride (Socian) ^‡ – 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.^[153]
• 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

• Iloperidone (Fanapt) – 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 (Invega) – Primary, active metabolite of risperidone that was approved in 2006.
• Perospirone ^† – Has a higher incidence of extrapyramidal side effects than other atypical antipsychotics.^[154]
• Risperidone (Risperdal) – 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 (Geodon) – Approved in 2004^[155] 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 (Latuda) – 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 (Caplyta)

Tricyclics

• Asenapine (Saphris) – Of the dibenzo-oxepino pyrrole class of atypical antipsychotics. Used for the treatment of schizophrenia and acute mania associated with bipolar disorder.
• Clozapine (Clozaril) – Of the dibenzodiazepine class of atypical antipsychotics. 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 (Zyprexa) – Of the theienobenzodiazepine class of atypical antipsychotics. 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 (Seroquel) – Of the dibenzothiazepine class of atypical antipsychotics. 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 and bipolar disorder (it treats mixed mood swings alone). It indirectly serves as a norepinephrine reuptake inhibitor by means of its active metabolite, norquetiapine.
• Zotepine – Of the dibenzothiepin class of 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-HT_2A 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 partial agonism^[156] as opposed to the D₂ and 5HT-_2A receptor antagonism of second-generation (atypical) antipsychotics and D2 antagonism of first-generation (typical) antipsychotics.^[15]

Benzisoxazoles/benzisothiazoles

• Lumateperone (Caplyta) – In December 2019, lumateperone, a presynaptic D₂ receptor partial agonist and postsynaptic D₂ receptor antagonist, received its first global approval in the USA for the treatment of schizophrenia in adults.^[157] In 2020 and 2021 FDA approved for depressive episodes associated with bipolar I or II disorder in adults, as monotherapy and as adjunctive therapy with lithium or valproate.

Phenylpiperazines/quinolinones

• Aripiprazole (Abilify) - Partial agonist at the D₂ receptor. Considered the prototypical third-generation antipsychotic.^[158]
• Aripiprazole lauroxil (Abilify Maintena) – Long-acting version of aripiprazole for injection.
• Brexpiprazole (Rexulti) – Partial agonist of the D₂ receptor. Successor of aripiprazole.
• Cariprazine (Vraylar, Reagila) – A D₃-preferring D_2/3 partial agonist.

Phenylpiperazines/benzoxazinones

• Brilaroxazine – A D_2/3/4 and 5-HT_1A partial agonist and 5-HT_2A/2B/7 antagonist

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.^[159][160]

In addition to the antagonistic effects of dopamine, antipsychotics (in particular atypical neuroleptics) also antagonize 5-HT_2A receptors. Different alleles of the 5-HT_2A receptor have been associated with schizophrenia and other psychoses, including depression.^[161][162] Higher concentrations of 5-HT_2A receptors in cortical and subcortical areas, in particular in the right caudate nucleus have been historically recorded.^[161]

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.^[163]

Atypical antipsychotic drugs have a similar blocking effect on D₂ receptors; however, most also act on serotonin receptors, especially 5-HT_2A and 5-HT_2C 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.^[164] 5-HT_2A antagonism increases dopaminergic activity in the nigrostriatal pathway, leading to a lowered extrapyramidal side effect liability among the atypical antipsychotics.^[164][165]

Through the ability of most antipsychotics to antagonize 5-HT_2A serotonin pathways enabling a sensitisation of postsynaptic serotonin receptors, MDMA exposure can be more intense because it has more excitatory receptors to activate. The same effect can be observed with the D₂ antagonizing with normal amphetamine (with this just being hypothetical as there is the fact that antipsychotics sensitize receptors,^[166] with exact these postsynaptic receptors (5-HT_2A, D₂) being flooded by the respective neurotransmitter (serotonine, dopamine) from amphetamine exposure).^[167][168]

Comparison of medications

Overview

Generic name Class Type Brand name(s) Launch Developer/Originator(s) Refs Amisulpride Benzamide Disputed Solian 1986 Sanofi-Synthélabo ^[169]^[170]^[171] Aripiprazole Phenylpiperazine/Quinolinone Atypical Abilify 2002 Otsuka/Bristol-Myers Squibb ^[169]^[172] Aripiprazole lauroxil Phenylpiperazine/Quinolinone Atypical Aristada 2015 Alkermes ^[173] Asenapine Tricyclic/Dibenzoxapinopyrrole Atypical Saphris/Sycrest 2009 Organon/Merck ^[169]^[174] Benperidol Butyrophenone Typical Anquil 1966 Janssen ^[169] Blonanserin Pyridinylpiperazine Atypical Lonasen 2008 Sumitomo Dainippon/Mitsubishi Tanabe ^[169]^[175] Brexpiprazole Phenylpiperazine/Quinolinone Atypical Rexulti 2015 Otsuka/Lundbeck ^[176] Bromperidol Butyrophenone Typical Impromem 1981 Janssen ^[169]^[172] Cariprazine Phenylpiperazine Atypical Vraylar/Reagila 2015 Gedeon Richter/Actavis ^[177] Carpipramine Tricyclic/Dibenzazepine Disputed Defecton/Prazinil 1977 Pierre Fabre ^[169] Chlorpromazine Tricyclic/Phenothiazine Typical Thorazine 1952 Rhône-Poulenc/GlaxoSmithKline ^[169]^[172] Chlorprothixene Tricyclic/Thioxanthene Disputed Truxal 1959 Roche ^[169]^[172]^[178] Clocapramine Tricyclic/Dibenzazepine Disputed Clofekton/Padrasen 1974 Yoshitomi ^[179] Clopenthixol Tricyclic/Thioxanthene Typical Sordinol/Ciatyl 1961 Lundbeck ^[180] Clorotepine Tricyclic/Dibenzothiepin Disputed Clotepin 1971 Spofa ^[181]^[182] Clotiapine Tricyclic/Dibenzothiazepine Disputed Etumine 1966 Sandoz/Wander ^[183]^[184] Clozapine Tricyclic/Dibenzodiazepine Atypical Clozaril 1972 Sandoz-Novartis ^[169]^[172] Cyamemazine Tricyclic/Phenothiazine Disputed Tercian 1972 Aventis ^[169]^[185] Droperidol Butyrophenone Typical Dridol/Droleptan/Inapsine 1963 Janssen-Cilag ^[169]^[186] Flupentixol Tricyclic/Thioxanthene Typical Fluanxol 1965 Lundbeck ^[169]^[187] Fluphenazine Tricyclic/Phenothiazine Typical Prolixin 1959 Bristol-Myers Squibb ^[169]^[172] Fluspirilene Diphenylbutylpiperidine Typical Imap 1970 Janssen ^[169] Haloperidol Butyrophenone Typical Haldol 1959 Janssen ^[169]^[172] Iloperidone Benzisoxazole Atypical Fanapt 2010 Novartis ^[169]^[188] Levomepromazine Tricyclic/Phenothiazine Disputed Nozinan/Levoprome 1957 Rhône-Poulenc ^[169]^[178]^[189] Levosulpiride Benzamide Disputed Levopraid 1987 Abbott ^[169] Loxapine Tricyclic/Dibenzoxazepine Disputed Loxitane/Loxapac 1975 Wyeth ^[169]^[172]^[190] Lurasidone Benzisothiazole Atypical Latuda 2010 Sumitomo Dainippon/Sunovion ^[191] Melperone Butyrophenone Disputed Buronil 1967 Lundbeck ^[172] Mesoridazine Tricyclic/Phenothiazine Typical Serentil 1967 Novartis-Boehringer ^[172] Molindone Dihydroindolone Disputed Moban 1975 Abbott ^[172] Mosapramine Tricyclic/Dibenzazepine Disputed Cremin 1991 Mitsubishi Pharma ^[169] Nemonapride Benzamide Disputed Emilace/Emirace 1991 Yamanouchi ^[169]^[192] Olanzapine Tricyclic/Thienobenzodiazepine Atypical Zyprexa 1996 Lilly ^[169]^[172] Paliperidone Benzisoxazole Atypical Invega 2007 Janssen-Cilag/Johnson & Johnson ^[169]^[193] Paliperidone palmitate Benzisoxazole Atypical Invega Sustenna/Xeplion 2009 Janssen-Cilag/Johnson & Johnson ^[194] Penfluridol Diphenylbutylpiperidine Typical Semap 1973 Janssen ^[195]^[196] Perazine Tricyclic/Phenothiazine Typical Taxilan 1958 Promonta ^[197] Periciazine Tricyclic/Phenothiazine Typical Neuleptil/Neulactil 1964 Rhône-Poulenc ^[169]^[198] Perospirone Benzisothiazole Atypical Lullan 2001 Sumitomo Dainippon/Mitsubishi Tanabe ^[169]^[199] Perphenazine Tricyclic/Phenothiazine Typical Trilafon 1957 Schering-Plough ^[169]^[172] Pimavanserin Dibenzylpiperidinylurea Atypical Nuplazid 2016 ACADIA Pharmaceuticals ^[200] Pimozide Diphenylbutylpiperidine Typical Orap 1969 Janssen ^[169]^[172] Pipamperone Butyrophenone Disputed Dipiperon 1961 Janssen ^[183]^[195] Pipotiazine Tricyclic/Phenothiazine Typical Piportil 1973 Rhône-Poulenc/Aventis ^[169]^[201] Prochlorperazine Tricyclic/Phenothiazine Typical Compazine 1956 Rhône-Poulenc/GlaxoSmithKline ^[169]^[172]^[189] Promazine Tricyclic/Phenothiazine Typical Sparine 1956 Wyeth ^[169] Quetiapine Tricyclic/Dibenzothiazepine Atypical Seroquel 1997 AstraZeneca ^[169]^[172] Remoxipride Benzamide Disputed Roxiam 1990 AstraZeneca ^[169]^[171]^[172] Risperidone Benzisoxazole Atypical Risperdal 1993 Janssen ^[169]^[172] Sertindole Imidazolidinone Atypical Serdolect 1996 Lundbeck ^[169]^[172] Spiperone Butyrophenone Typical Spiropitan 1969 Eisai ^[202] Sulpiride Benzamide Disputed Dogmatil 1968 Delagrange/Fujisawa ^[169]^[171]^[172] Sultopride Benzamide Disputed Barnetil 1976 Delagrange/Sanofi-Synthélabo ^[169]^[203] Thioridazine Tricyclic/Phenothiazine Typical Melleril 1958 Novartis ^[169]^[172] Tiapride Benzamide Disputed Tiapridal 1975 Sanofi-Synthélabo ^[169] Tiotixene Tricyclic/Thioxanthene Typical Navane 1967 Pfizer ^[169]^[172]^[204] Trifluoperazine Tricyclic/Phenothiazine Typical Stelazine 1958 GlaxoSmithKline ^[169]^[172] Triflupromazine Tricyclic/Phenothiazine Typical Vesprin 1957 Bristol-Myers Squibb ^[169] Veralipride Benzamide Disputed Agreal 1980 Sanofi-Synthélabo ^[169] Ziprasidone Benzisothiazole Atypical Geodon 2000 Pfizer ^[169]^[172] Zotepine Tricyclic/Dibenzothiepin Atypical Zoleptil 1982 Fujisawa ^[169]^[172] Zuclopenthixol Tricyclic/Thioxanthene Typical Clopixol/Cisordinol 1978 Lundbeck ^[169]^[180]^[187]

Tolerability (as propensity for adverse effects)
Generic name ^[17]^[19]^[37]^[205]^[206]	Discontinuation rate^[37] (OR with 95% CI)	Anticholinergic effects	Sedation	EPSE	Weight Gain	Metabolic AEs	QTc prolongation (ORs & 95% CIs)	PE	Hypotension	Notes (e.g., notable AEs*)
Amisulpride	0.43 (0.32–0.57)	-	-	+	+	+/-	+++ 0.66 (0.39–0.91)	+++/++	-	Torsades de Pointes common on overdose.^[207] Has a comparatively low penetrability of the blood–brain barrier.
Amoxapine	?	++	++	+/-	++/+	++/+	++/+	++/+	++/+	Amoxapine is also an antidepressant. Very toxic in overdose due to the potential for renal failure and seizures.
Aripiprazole	0.61 (0.51–0.72)	-	+	+/- (akathisia mostly)	+	+/-	- 0.01 (−0.13 to 0.15)	- (can reduce prolactin levels)	-	Only clinically utilised antipsychotic that does not act by antagonising the D2 receptor and rather partially agonises this receptor.
Asenapine	0.69 (0.54–0.86)	-	++	+	+	+/-	++/+ 0.30 (−0.04 to 0.65)	+	+	Oral hypoesthesia. Has a complex pharmacologic profile.
Blonanserin^[208]^[209]	~0.7	+	+	++/+	+/-	+/-	-	++/+	+/-	Only used in a few East Asian countries.
Chlorpromazine	0.65 (0.5–0.84)	+++	+++	++	++	++	++	+++	+++	First marketed antipsychotic, sort of the prototypical low-potency first-generation (typical) antipsychotic.
Clozapine	0.46 (0.32–0.65)	+++	+++	-	+++	+++	+	-	+++	Notable AEs: Agranulocytosis, neutropaenia, leukopaenia and myocarditis. Dose-dependent seizure risk.^[210] Overall the most effective antipsychotic, on average. Usually reserved for treatment-resistant cases or highly suicidal patients.
Droperidol	?	+/-	+/-	+++	+/-	+/-	?	+++	?	Mostly used for postoperative nausea and vomiting.
Flupenthixol	?	++	+	++	++	++	+	+++	+	Also used in lower doses for depression.
Fluphenazine	0.69 (0.24–1.97)^[211]	++	+	+++	+	+	+	+++	+	High-potency first-generation (typical) antipsychotic.
Haloperidol	0.8 (0.71–0.90)	+	+	+++	+	+/-	+ 0.11 (0.03–0.19)	+++	+	Prototypical high-potency first-generation (typical) antipsychotic.
Iloperidone	0.69 (0.56–0.84)	-	+/-	+	++	++	++ 0.34 (0.22–0.46)	++/+	+	?
Levomepromazine	?	+++	+++	++/+	++	++	?	+++	+++	Also used as an analgesic, agitation, anxiety and emesis.
Loxapine	0.52 (0.28–0.98)^[212]	+	++	+++	+	+/-	?	+++	++	?
Lurasidone	0.77 (0.61–0.96)	-	-	++/+	-	-	- −0.10 (−0.21 to 0.01)	++/+	-	May be particularly helpful in ameloriating the cognitive symptoms of schizophrenia, likely due to its 5-HT7 receptor.^[213]
Melperone	?	-	+/-	-	+/-	+/-	++	-	++/+	Several smaller low-quality clinical studies have reported its efficacy in the treatment of treatment-resistant schizophrenia. Only approved for use in a few European countries. It is known that off-licence prescribing of melperone is occurring in the United Kingdom.^[214] Is a butyrophenone, low-potency atypical antipsychotic that has been tried as a treatment for Parkinson's disease psychosis, although with negative results.
Molindone^[215]	?	-	++/+	+	-	-	?	+++	+/-	Withdrawn from the market. Seems to promote weight loss (which is rather unusual for an antipsychotic seeing how they tend to promote weight gain).^[215]
Olanzapine	0.46 (0.41–0.52)	+	++	+	+++	+++	+ 0.22 (0.11–0.31)	+	+	?
Paliperidone	0.48 (0.39–0.58)	-	-	++/+ (dose dependent)	++	+	– 0.05 (−0.18 to 0.26)	+++	++	Active metabolite of risperidone.
Perazine	0.62 (0.4–1.10)^[216]	?	?	?	?	?	?	?	?	Limited data available on adverse effects.
Periciazine	?	+++	+++	+	++	+	?	+++	++	Also used to treat severe anxiety. Not licensed for use in the US.
Perospirone^[217]	?	+/-	+	++/+^[218]	+/-	?	-	++/+	-	Usually grouped with the atypical antipsychotics despite its relatively high propensity for causing extrapyramidal side effects.^[218]
Perphenazine	0.30 (0.04–2.33)^[219]	+	+	+++	+	+	+	+++	+	Has additional antiemetic effects.
Pimozide	1.01 (0.30–3.39)^[220]	+	+	+	+	+	+++	+++	+	High potency first-generation (typical) antipsychotic.
Pipotiazine	?	++	++	++	++	+	?	+++	++	Only available in the UK.
Prochlorperazine	?	?	?	+++	?	?	+	+++	?	Primarily used in medicine as an antiemetic.
Quetiapine	0.61 (0.52–0.71)	++/+	++	-	++	++/+	+ 0.17 (0.06–0.29)	-	++	Binds to the D2 receptor in a hit and run fashion. That is it rapidly dissociates from said receptor and hence produces antipsychotic effects but does not bind to the receptor long enough to produce extrapyramidal side effects and hyperprolactinaemia.
Remoxipride	?	-	+/-	-	+/-	+/-	-	-	-	Removed from the market amidst concerns about an alarmingly high rate of aplastic anaemia.
Risperidone	0.53 (0.46–0.60)	-	++/+ (dose-dependent)	++	++	++/+	++ 0.25 (0.15–0.36)	+++	++	?
Sertindole	0.78 (0.61–0.98)	-	-	-	++	++/+	+++ 0.90 (0.76–1.02)	-	+++	Not licensed for use in the US.
Sulpiride	1.00 (0.25–4.00)^[221]	-	-	+	+	+/-	+	+++/++	-	Not licensed for use in the US.
Thioridazine	0.67 (0.32–1.40)^[222]	+++	+++	+	++	++	+++	+++	+++	Dose-dependent risk for degenerative retinopathies.^[223] Found utility in reducing the resistance of multidrug and even extensively resistant strains of tuberculosis to antibiotics.
Tiotixene	?	-	+	+++	++	++/+	+	+++	+	?
Trifluoperazine	0.94 (0.59–1.48)^[224]	+/-	+	+++	+	+/-	?	+++	+	?
Ziprasidone	0.72 (0.59–0.86)	-	++	+	-	-	++ 0.41 (0.31–0.51)	++/+	+	?
Zotepine	0.69 (0.41–1.07)	+	+++	++	+++/++	+++/++	++	+++	++	Dose-dependent risk of seizures.^[225] Not licensed for use in the US.
Zuclopenthixol	?	++	++	+++	++	++	?	+++	+	Not licensed for use in the US.
Note: "Notable" is to mean side-effects that are particularly unique to the antipsychotic drug in question. For example, clozapine is notorious for its ability to cause agranulocytosis. If data on the propensity of a particular drug to cause a particular AE is unavailable an estimation is substituted based on the pharmacologic profile of the drug. Acronyms used: AE – Adverse effect OR – Odds ratio CI – Confidence Interval EPSE – Extrapyramidal Side Effect QTc – Corrected QT interval PE – Prolactin elevation Legend: - very low propensity for this AE + low propensity/severity for this AE ++ moderate propensity/severity for this AE +++ high propensity/severity for this AE

Efficacy
Generic drug name	Schizophrenia^[17]^[37]	Mania^[226]^[227]	Bipolar depression^[228]	Bipolar maintenance^[229]^[230]	Adjunct in major depression^[231]
Amisulpride	+++	?	?	?	? (+++ in dysthymia)
Aripiprazole	++	++	-	++ (prevents manic and mixed but not depressive episodes)	+++
Asenapine	++/+	++	?	++	?
Chlorpromazine	++	?	?	?	?
Clozapine	+++	+++^[232]	+++	+++^[233]	+++^[234]
Haloperidol	++	+++	?	?	?
Iloperidone	+	?	?	?	?
Loxapine	+++/++	+++ (only in the treatment of agitation)	?	?	?
Lurasidone	+	?	+++	?	?
Melperone	+++	?	?	?	?
Olanzapine	+++	+++/++	++	++	++
Paliperidone	++	+++/++	?	?	?
Perospirone^[235]	+	?	?	?	?
Quetiapine	++	++	+++	+++	++
Risperidone	+++	+++	-	++	+++
Sertindole	++	?	?	?	?
Ziprasidone	++/+	+	?	+	?
Zotepine	++	?	?	?	?

Binding affinity

Ki [nM] toward cloned human receptors (unless otherwise specified)^[Note 1] Drug name^[124]^[236] SERT 5-HT1A 5-HT2A 5-HT2C 5-HT6 5-HT7 α1A α2A α2C NET D1 D2 D3 D4 5-HT2A/D2 H1 M1 M3 Amisulpride >10,000 >10,000 8,304 >10,000 4,154 73.5 >10,000 1,114 1,540 >10,000 >10,000 2.2 2.4 2,370 3774.5 >10,000 >10,000 >10,000 Aripiprazole 1,081 5.6 8.7 22.4 642.4 9.97 25.85 74.1 37.63 2091.5 1,173.5 1.64 5.35 514 5.3 27.93 6,778 4,678 Asenapine^[237] ND 2.5 0.06 0.03 0.25 0.13 1.2 1.2 1.2 ND 1.4 1.3 0.42 1.1 0.0462 1.0 8,128 8,128 Blonanserin^[238] ND 804 0.812 26.4 41.9 183 26.7 (RB) 530 (RC) ND ND 1,070 0.142 0.494 150 5.72 765 100 ND Brexpiprazole ND 0.12 0.47 ND 58 3.7 3.8 15 0.59 ND 160 0.3 1.1 6.3 1.567 19 ND >10,000 N-DEBN^[208] ND ND 1.28 4.50 5.03 206 (RC) ND ND ND ND 1,020 1.38 0.23 ND 0.93 ND ND ND Chlorpromazine 1,296 2,115.5 4.5 15.6 17.0 28.4 0.28 184 46 2,443 76.3 1.40 4.65 5.33 3.21 3.09 32.3 57.0 Clozapine 1,624 123.7 5.35 9.44 13.5 17.95 1.62 37 6.0 3,168 266.3 157 269.1 26.4 0.0341 1.13 6.17 19.25 Norclozapine 316.6 13.9 10.9 11.9 (RC) 11.6 60.1 104.8 137.6 117.7 493.9 14.3 94.5 153 63.94 0.115 3.4 67.6 95.7 cis-Flupenthixol ND 8,028 87.5 (HFC) 102.2 (RC) ND ND ND ND ND ND 3.5 0.35 1.75 66.3 250 0.86 ND ND Fluphenazine 5,950 1,039.9 37.93 982.5 34.67 8.00 6.45 314.1 28.9 3,076 17.33 0.30 1.75 40.0 126.4 14.15 1,095 1,441 Haloperidol 3,256 2,066.83 56.81 4,801 5,133 377.6 12.0 801.5 403 2,112 121.8 0.7 3.96 2.71 81.2 1698 >10,000 >10,000 Iloperidone ND 93.21 1.94 147 63.09 112 0.3 160 16.2 1479 129.32 10.86 10.55 13.75 0.179 12 4,898 >10,000 Loxapine >10,000 2,456 6.63 13.25 31.0 87.6 31.0 150.9 80.0 5,698 54 28.1 19.33 7.80 0.236 4.90 119.45 211.33 Amoxapine 58 ND 0.5 2.0 (RC) 50 40.21 50 ND ND 16 ND 20.8 21.0 21.0 0.0240 25 1,000 1,000 Lurasidone^[238]^[239] ND 6.8 2.0 415 ND 0.5 48 1.6 10.8 ND 262 1.7 ND ND 1.18 >10,000 >10,000 >10,000 Melperone ND 2,200 (HB) 230 2,100 (HB) 1,254 (RC) 578 (HB) 180 (HB) 150 (HB) ND ND ND 194 8.95 555 1.186 580 >10,000 >10,000 Molindone ND 3,797 3773 >10,000 1,008 3,053 2,612 1,097 172.6 ND ND 6.0 72.5 2,950 628.83 2,130 ND >10,000 Olanzapine 3,676 2282 3.73 10.2 8.07 105.2 112 314 28.9 >10,000 70.33 34.23 47.0 14.33 0.109 2.19 2.5 56.33 Paliperidone 3,717 616.6 0.71 48 2,414 2.7 2.5 17.35 7.35 >10,000 41.04 0.7 0.5 54.3 1.104 18.8 >10,000 >10,000 Perphenazine ND 421 5.6 132 17 23 10 810.5 85.2 ND ND 0.14 0.13 17 40 8 1,500 1,848 Pimozide ND 650 48.35 2,112 71 0.5 197.7 1,593 376.5 ND >10,000 1.45 0.25 1.8 33.34 692.2 800 (HB) 1,955 Prochlorperazine ND 5,900 (HC) 15 (HC) 122 148 (RC) 196 (RC) 23.8 (HB) 1,694.91 (HB) ND ND ND 0.65 2.90 5.40 23.1 18.86 (HB) 555.55 (HB) ND Quetiapine >10,000 394.2 912 1,843 948.75 307.6 22 3,630 28.85 >10,000 994.5 379 340 2,019 2.41 6.90 489 1631.5 Norquetiapine^[240] ND 45 48 107 ND 76 144 237 ND 12 99.8 (RC) 196 ND ND 0.245 3.5 38.3 (RC) ND Risperidone >10,000 422.88 0.17 12 2057.17 6.6 5 16.5 1.3 >10,000 243.53 3.57 2.0 4.66 0.0476 20.05 >10,000 >10,000 Sertindole ND 280 0.39 0.9 5.4 28 1.8 640 450 ND ND 2.35 2.30 4.92 0.166 130 >5,000 2,692 Sulpiride ND >10,000 >10,000 (RC) >10,000 (RC) 5,000 (RC) 4,000 (RC) >10,000 (RB) 4,893 (RB) ND ND >10,000 9.80 8.05 54 >1,000 >10,000 (RB) >10,000 (RB) >10,000 (RB) Thioridazine 1,259 144.35 27.67 53 57.05 99 3.15 134.15 74.9 842 94.5 2.20 1.50 6.00 12.58 16.5 12.8 29 Tiotixene 3,878 410.2 50 1355.5 245.47 15.25 11.5 79.95 51.95 >10,000 51 0.12 0.40 203 416.7 8 >10,000 >10,000 Trifluoperazine ND 950 74 378 144 290.8 24 653.7 391.5 ND ND 1.12 ND 38.1 66.07 63 ND 1,001 Ziprasidone 112 54.67 0.73 13 60.95 6.31 18 160 68 44 30 4.35 7.85 52.9 0.1678 62.67 >10,000 >10,000 Zotepine 151 470.5 2.7 3.2 6 12 7 208 106 530 71 25 6.4 18 0.108 3.21 18 73 Acronyms used: HFC – Human frontal cortex receptor RB – Rat brain receptor RC – Cloned rat receptor ND – No data HB – Human brain receptor HC – Human cortex receptor N-DEBN – N-desethylblonanserin

Pharmacokinetics

Drug^[241]^[242]^[243]^[244] Bioavailability t1/2 parent drug (active metabolite) Protein binding tmax Cmax Vd Excretion Routes Metabolism enzymes^[124] Active metabolites Amisulpride 48% 12 h 16% 3–4 h 54 ± 4 ng/mL 5.8 L/kg Faeces (20%), urine (50%, when given IV) Oral ? None Aripiprazole 87% (Oral), 100% (IM) 75 h (94 h) 99% 3–5 h ? 4.9 L/kg Faeces (55%), urine (25%) Oral, IM (including depot) CYP2D6, CYP3A4 Dehydroaripiprazole Asenapine 35% (sublingual) 24 h 95% 0.5–1.5 h 4 ng/mL 20–25 L/kg Urine (50%), faeces (40%) Sublingual CYP1A2, UGT1A4, CYP2D6 None Blonanserin^[208]^[209]^[245] 55% 10.7-16.2 h (single dosing), 67.9 h (repeated dosing) ≥ 99.7% 1.5-2 h 0.14-0.76 ng/mL (0.57 ng/mL for repeated dosing) 8560-9500 L Urine (59%), faeces (30%) Oral CYP3A4 N-desethylblonanserin Chlorpromazine 20% 30 h 92–97% ? ? 20 L/kg Urine Oral, IM, IV CYP2D6 Several active metabolites Clozapine 50–60% 12 h 97% 1.5–2.5 h 102-771 ng/mL 4.67 L/kg Urine (50%), faeces (30%) Oral CYP1A2, CYP2D6, CYP3A4 Norclozapine Droperidol ? 2 h (8–12 h) Extensive 60 min (IM) ? 2 L/kg (adults), 0.58 L/kg (children) Urine (75%), faeces (22%) IM, IV ? None Flupentixol 40–55% (Oral) 35 h ? 7 days (depot) ? 12–14 L/kg Urine Oral, IM (including depot) ? None Fluphenazine 2.7% (Oral) 14–16 h, 14 days (depot) ? 2 h (Oral), 8–10 h (depot) ? ? Urine, faeces Oral, IM (including depot) ? None Haloperidol 60–70% (Oral) 10–20 h (short-acting IM), 3 weeks (depot) 92% 2–6 h (Oral), 10–20 min (short-acting IM), 6–7 days (depot) ? 8–18 L/kg Urine (30%), faeces (15%) Oral, IM, IV CYP3A4 None Iloperidone 96% ? 95% 2–4 h ? 1340–2800 L Urine (45–58%), faeces (20–22%) Oral CYP3A4, CYP2D6 None notable. Levomepromazine ? 30 h ? 2–3 h ? ? Urine, faeces IM, IV ? Methotrimeprazine sulfoxide Loxapine High 6–8 h (Inhaled), 4–12 h (Oral) 96.6% 2 min (inhaled), 2 h (oral), 5 h (IM) 257 ng/mL (inhaled), 6–13 ng/mL (Oral) ? Urine (56–70%), faeces [Only oral data available] Oral, IM, Inhalation CYP1A2, CYP3A4, CYP2D6 Amoxapine (a tricyclic antidepressant), 7-OH loxapine, 8-OH loxapine Lurasidone 9–19% 18 h 99% 1–3 h ? 6173 L Urine (9%), faeces (80%) Oral CYP3A4 2 active Melperone^[246] 54% (Oral via syrup), 65% (Oral via tablets), 87% (IM) 2.1-6.4 h (Oral), 6.6 ± 3.7 h (IM) 50% 1.6-2.4 h (Oral, tablets), 1 h (Oral, syrup) 1132 ± 814 ng/mL (25 mg, orally), 2228–3416 ng/mL (50 mg, orally), 89539 ± 37001 ng/mL (100 mg, orally) 9.9 ± 3.7 L/kg (10 mg), 7 ± 1.61 L/kg (20 mg) Urine (70% as metabolites, 5.5–10.4% as parent drug) Oral, IM ? None Olanzapine 87% (Oral) 30 h 93% 6 h (Oral), 15–45 min (short-acting IM), 7 days (depot) 4–20.4 mg/mL^[247] 1000 L Urine (57%), faeces (30%) Oral, IM (including depot) CYP1A2 None Paliperidone 28% (Oral) 23 h (Oral), 25–49 days (IM) 74% 24 h (Oral), 13 days (IM) 8.85-11.7 ng/mL^[248] 390-487 L Urine (80%), faeces (11%) Oral, IM (depot) CYP3A4, CYP2D6 None Periciazine ? 12 h ? 2 h 150 ng/mL ? Urine Oral ? ? Perospirone^[154] ? 1.9–2.5 h 92% 1.5 h 5.7 ng/mL ? Urine (0.4% as unchanged drug) Oral ? None Perphenazine ? 9–12 h (10–19 h) ? 1–3 h; 2–4 h (metabolite) 0.984 ng/mL; 0.509 ng/mL ? Urine, faeces Oral CYP2D6 7-OH perphenazine Pimozide 40–50% 55 h ? 6–8 h 4–19 ng/mL (dose-dependent) ? Urine Oral CYP3A4, CYP2D6 None Prochlorperazine 12.5% 6.8–9 h High ? ? 12.9–17.7 L/h Urine, bile Oral, IM, IV ? N-desmethylprochlorperazine Quetiapine 100% 6 h (IR), 7 h (XR); active metabolite: 12 h 83% 1.5 h (IR), 6 h (XR) @ 250 mg q8hr 778 ng/mL (male), 879 ng/mL (female)^[249] 6-14 L/kg Urine (73%), faeces (20%) Oral CYP3A4 Norquetiapine (a norepinephrine reuptake inhibitor and 5-HT1A receptor partial agonist) Risperidone 70% 3–17 h (24 h) 90% (active metabolite: 77%) 3–17 h ? 1–2 L/kg Urine (70%), faeces (14%) Oral, IM (including depot) CYP2D6 Paliperidone Sertindole ? 3 days 99.5% 10 h ? 20 L/kg Urine (4%), faeces (46–56%) Oral CYP2D6 None Sulpiride^[250] 27 ± 9% 8 h 40% 3-6 h ? 2.72 ± 0.66 L/kg Urine, faeces Oral ? None Thioridazine ? 24 h 95% ? ? ? ? Oral CYP2D6 None Tiotixene ? 24 h 90% ? ? ? ? Oral CYP1A2 None Trifluoperazine ? 24 h ? ? ? ? ? Oral ? None Ziprasidone 60% (Oral), 100% (IM) 7 h (Oral), 2–5 h (IM) 99% 6–8 h (Oral), ≤ 60 min (IM) ? 1.5 L/kg Faeces (66%), urine (20%) Oral, IM CYP3A4, CYP1A2 None Zotepine^[251]^[252] 7-13% 13.7-15.9 h (12 h) 97% 1-4 h 31-240 10 L/kg Urine (17%) Oral CYP1A2, CYP3A4 Norzotepine (a norepinephrine reuptake inhibitor) Zuclopenthixol 49% 20 h 98% 2–12 h (mean: 4 h) ? 20 L/kg Faeces, urine (10%) Oral, IM (including depot) CYP2D6 None

• v
• t
• e

Pharmacokinetics of long-acting injectable antipsychotics

Medication	Brand name	Class	Vehicle	Dosage	Tmax	t1/2 single	t1/2 multiple	logP^c	Ref
Aripiprazole lauroxil	Aristada	Atypical	Water^a	441–1064 mg/4–8 weeks	24–35 days	?	54–57 days	7.9–10.0
Aripiprazole monohydrate	Abilify Maintena	Atypical	Water^a	300–400 mg/4 weeks	7 days	?	30–47 days	4.9–5.2
Bromperidol decanoate	Impromen Decanoas	Typical	Sesame oil	40–300 mg/4 weeks	3–9 days	?	21–25 days	7.9	^[253]
Clopentixol decanoate	Sordinol Depot	Typical	Viscoleo^b	50–600 mg/1–4 weeks	4–7 days	?	19 days	9.0	^[254]
Flupentixol decanoate	Depixol	Typical	Viscoleo^b	10–200 mg/2–4 weeks	4–10 days	8 days	17 days	7.2–9.2	^[254]^[255]
Fluphenazine decanoate	Prolixin Decanoate	Typical	Sesame oil	12.5–100 mg/2–5 weeks	1–2 days	1–10 days	14–100 days	7.2–9.0	^[256]^[257]^[258]
Fluphenazine enanthate	Prolixin Enanthate	Typical	Sesame oil	12.5–100 mg/1–4 weeks	2–3 days	4 days	?	6.4–7.4	^[257]
Fluspirilene	Imap, Redeptin	Typical	Water^a	2–12 mg/1 week	1–8 days	7 days	?	5.2–5.8	^[259]
Haloperidol decanoate	Haldol Decanoate	Typical	Sesame oil	20–400 mg/2–4 weeks	3–9 days	18–21 days		7.2–7.9	^[260]^[261]
Olanzapine pamoate	Zyprexa Relprevv	Atypical	Water^a	150–405 mg/2–4 weeks	7 days	?	30 days	–
Oxyprothepin decanoate	Meclopin	Typical	?	?	?	?	?	8.5–8.7
Paliperidone palmitate	Invega Sustenna	Atypical	Water^a	39–819 mg/4–12 weeks	13–33 days	25–139 days	?	8.1–10.1
Perphenazine decanoate	Trilafon Dekanoat	Typical	Sesame oil	50–200 mg/2–4 weeks	?	?	27 days	8.9
Perphenazine enanthate	Trilafon Enanthate	Typical	Sesame oil	25–200 mg/2 weeks	2–3 days	?	4–7 days	6.4–7.2	^[262]
Pipotiazine palmitate	Piportil Longum	Typical	Viscoleo^b	25–400 mg/4 weeks	9–10 days	?	14–21 days	8.5–11.6	^[255]
Pipotiazine undecylenate	Piportil Medium	Typical	Sesame oil	100–200 mg/2 weeks	?	?	?	8.4
Risperidone	Risperdal Consta	Atypical	Microspheres	12.5–75 mg/2 weeks	21 days	?	3–6 days	–
Zuclopentixol acetate	Clopixol Acuphase	Typical	Viscoleo^b	50–200 mg/1–3 days	1–2 days	1–2 days		4.7–4.9
Zuclopentixol decanoate	Clopixol Depot	Typical	Viscoleo^b	50–800 mg/2–4 weeks	4–9 days	?	11–21 days	7.5–9.0
Note: All by intramuscular injection. Footnotes: ^a = Microcrystalline or nanocrystalline aqueous suspension. ^b = Low-viscosity vegetable oil (specifically fractionated coconut oil with medium-chain triglycerides). ^c = Predicted, from PubChem and DrugBank. Sources: Main: See template.

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^[263]

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".^[264] 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.^[265]

Until the 1970s there was considerable debate within psychiatry on the most appropriate term to use to describe the new drugs.^[16] In the late 1950s the most widely used term was "neuroleptic", followed by "major tranquilizer" and then "ataraxic".^[16] The first recorded use of the term tranquilizer dates from the early nineteenth century.^[266] 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.^[267] The word neuroleptic was coined in 1955 by Delay and Deniker after their discovery (1952) of the antipsychotic effects of chlorpromazine.^[16] 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.^[264] 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.^[268] This term derived from the Greek adjective "ἀτάρακτος" (ataraktos), which means "not disturbed, not excited, without confusion, steady, calm".^[16] 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.^[16] 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.^[16] 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.^[269][270] 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.^[16]

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.^[271][272]

Antipsychotics are a type of psychoactive or psychotropic medication.^[273][274]

Sales

Antipsychotics were once among the biggest selling and most profitable of all drugs, generating $22 billion in global sales in 2008.^[275] 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.^[276] By 2008, sales in the US reached $14.6 billion, the biggest selling drugs in the US by therapeutic class.^[277]

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.^[278]

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.^{[279][280][281]}

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.^[282]

Recreational use

Certain second-generation antipsychotics are misused or abused for their sedative, tranquilizing, and (paradoxically) "hallucinogenic" effects.^[283] The most commonly implicated second-generation antipsychotic is quetiapine.^[283] 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.^[283] Olanzapine, another sedating second-generation antipsychotic, has also been misused for similar reasons.^[283] 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.^[283]

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.^[284]

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.^[285] 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.^[286][287] 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.^[288]

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.^[289] 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.^[289] In addition, AstraZeneca faces numerous personal-injury lawsuits from former users of Seroquel (quetiapine), amidst federal^{[clarification needed]} investigations of its marketing practices.^[290] 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.^[275]

Harvard University medical professor Joseph Biederman conducted research on bipolar disorder in children that led to an increase in such diagnoses. A 2008 Senate^[which?] 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.^[289]

Pharmaceutical companies have also been accused of attempting to set the mental health agenda through activities such as funding consumer advocacy groups.^[291]

Special populations

It is recommended that persons with dementia who exhibit behavioral and psychological symptoms should not be given antipsychotics before trying other treatments.^{[292][needs update]} 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.^[292] 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.^[292] Elderly persons often have their dementia treated first with antipsychotics and this is not the best management strategy.^[293]

See also

• List of investigational antipsychotics
• Antipsychotic switching

Notes

1. Bolded drug names indicate drugs that are metabolites of clinically-marketed antipsychotics.

References

1. Finkel R, Clark MA, Cubeddu LX (2009). Pharmacology. Lippincott Williams & Wilkins. p. 151. ISBN 978-0-7817-7155-9. from the original on 1 April 2017.
2. Burnett GB (1975). "The assessment of thiothixene in chronic schizophrenia. A double-blind controlled trial". Dis Nerv Syst. 36 (11): 625–9. PMID 1102277.
3. Bartoli F, Cavaleri D, Callovini T, Riboldi I, Crocamo C, D'Agostino A, Martinotti G, Bertolini F, Ostuzzi G, Barbui C, Carrà G (March 2022). "Comparing 1-year effectiveness and acceptability of once-monthly paliperidone palmitate and aripiprazole monohydrate for schizophrenia spectrum disorders: Findings from the STAR Network Depot Study". Psychiatry Research. 309: 114405. doi:10.1016/j.psychres.2022.114405. PMID 35093701. S2CID 246054926.
4. Lally J, MacCabe JH (June 2015). "Antipsychotic medication in schizophrenia: a review". British Medical Bulletin. 114 (1): 169–79. doi:10.1093/bmb/ldv017. PMID 25957394. Antipsychotic medications are mainstays in the treatment of schizophrenia and a range of other psychotic disorders.
5. Grande I, Berk M, Birmaher B, Vieta E (April 2016). "Bipolar disorder". Lancet. 387 (10027): 1561–1572. doi:10.1016/S0140-6736(15)00241-X. PMID 26388529. S2CID 205976059.
6. Ho BC, Andreasen NC, Ziebell S, Pierson R, Magnotta V (February 2011). "Long-term antipsychotic treatment and brain volumes: a longitudinal study of first-episode schizophrenia". Archives of General Psychiatry. 68 (2): 128–137. doi:10.1001/archgenpsychiatry.2010.199. PMC 3476840. PMID 21300943.
7. Moncrieff J, Leo J (September 2010). "A systematic review of the effects of antipsychotic drugs on brain volume". Psychological Medicine. 40 (9): 1409–1422. doi:10.1017/S0033291709992297. PMID 20085668. S2CID 23522488.
8. Chopra S, Fornito A, Francey SM, O'Donoghue B, Cropley V, Nelson B, et al. (July 2021). "Differentiating the effect of antipsychotic medication and illness on brain volume reductions in first-episode psychosis: A Longitudinal, Randomised, Triple-blind, Placebo-controlled MRI Study". Neuropsychopharmacology. 46 (8): 1494–1501. doi:10.1038/s41386-021-00980-0. PMC 8209146. PMID 33637835.
9. Lawrie SM, Abukmeil SS (1998). "Brain abnormality in schizophrenia". British Journal of Psychiatry. 172 (2): 110–120. doi:10.1192/bjp.172.2.110. ISSN 0007-1250. PMID 9519062. S2CID 23604963.
10. please see Chopra et al 2021: Strengths and limitations "only examined risperidone and paliperidone"
11. please see Chopra et al 2021: Method Study design
12. please see Chopra et al 2021: Introduction, 3rd paragraph, Lieberman JA, et al. 2005 & Shao Y et al 2015, and Chopra et al: Are antipsychotics neuroprotective? 1st paragraph last sentence
13. Shen WW (December 1999). "A history of antipsychotic drug development". Comprehensive Psychiatry. 40 (6): 407–14. doi:10.1016/s0010-440x(99)90082-2. PMID 10579370.
14. Aringhieri S, Carli M, Kolachalam S, Verdesca V, Cini E, Rossi M, et al. (December 2018). "Molecular targets of atypical antipsychotics: From mechanism of action to clinical differences". Pharmacology & Therapeutics. 192: 20–41. doi:10.1016/j.pharmthera.2018.06.012. PMID 29953902. S2CID 49602956.
15. Mailman RB, Murthy V (2010). "Third generation antipsychotic drugs: partial agonism or receptor functional selectivity?". Current Pharmaceutical Design. 16 (5): 488–501. doi:10.2174/138161210790361461. PMC 2958217. PMID 19909227.
16. King C, Voruganti LN (May 2002). "What's in a name? The evolution of the nomenclature of antipsychotic drugs". Journal of Psychiatry & Neuroscience. 27 (3): 168–175. PMC 161646. PMID 12066446.
17. Leucht S, Corves C, Arbter D, Engel RR, Li C, Davis JM (January 2009). "Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis". Lancet. 373 (9657): 31–41. doi:10.1016/S0140-6736(08)61764-X. PMID 19058842. S2CID 1071537.
18. Goikolea JM, Colom F, Torres I, Capapey J, Valentí M, Undurraga J, Grande I, Sanchez-Moreno J, Vieta E (January 2013). "Lower rate of depressive switch following antimanic treatment with second-generation antipsychotics versus haloperidol". Journal of Affective Disorders. 144 (3): 191–8. doi:10.1016/j.jad.2012.07.038. PMID 23089129.
19. Taylor D, Paton C, Kapur S, Taylor D (2012). The Maudsley prescribing guidelines in psychiatry (11th ed.). Chichester, West Sussex, UK: Wiley-Blackwell. ISBN 978-0-470-97948-8.
20. "American Psychiatric Association Five Things Physicians and Patients Should Question". Choosing Wisely. from the original on 3 December 2013. Retrieved 23 September 2013.
21. Budman CL (July 2014). "The role of atypical antipsychotics for treatment of Tourette's syndrome: an overview". Drugs. 74 (11): 1177–1193. doi:10.1007/s40265-014-0254-0. PMID 25034359. S2CID 24378317.
22. Basson R, Gilks T (1 January 2018). "Women's sexual dysfunction associated with psychiatric disorders and their treatment". Women's Health. 14: 1745506518762664. doi:10.1177/1745506518762664. PMC 5900810. PMID 29649948.
23. Kreys TJ, Phan SV (February 2015). "A literature review of quetiapine for generalized anxiety disorder". Pharmacotherapy. 35 (2): 175–188. doi:10.1002/phar.1529. PMID 25689246. S2CID 24744675.
24. "Psychosis and schizophrenia in adults (CG178)". 12 February 2014. from the original on 4 March 2014.
25. "American Psychiatric Association Practice Guidelines". Psychiatry Online.
26. Barnes TR (May 2011). "Evidence-based guidelines for the pharmacological treatment of schizophrenia: recommendations from the British Association for Psychopharmacology". Journal of Psychopharmacology. 25 (5): 567–620. doi:10.1177/0269881110391123. PMID 21292923. S2CID 40089561.
27. Miyamoto S, Miyake N, Jarskog LF, Fleischhacker WW, Lieberman JA (December 2012). "Pharmacological treatment of schizophrenia: a critical review of the pharmacology and clinical effects of current and future therapeutic agents". Molecular Psychiatry. 17 (12): 1206–27. doi:10.1038/mp.2012.47. PMID 22584864.
28. Hartling L, Abou-Setta AM, Dursun S, Mousavi SS, Pasichnyk D, Newton AS (October 2012). "Antipsychotics in adults with schizophrenia: comparative effectiveness of first-generation versus second-generation medications: a systematic review and meta-analysis". Annals of Internal Medicine. 157 (7): 498–511. doi:10.7326/0003-4819-157-7-201210020-00525. PMID 22893011.
29. Furukawa TA, Levine SZ, Tanaka S, Goldberg Y, Samara M, Davis JM, Cipriani A, Leucht S (January 2015). "Initial severity of schizophrenia and efficacy of antipsychotics: participant-level meta-analysis of 6 placebo-controlled studies". JAMA Psychiatry. 72 (1): 14–21. doi:10.1001/jamapsychiatry.2014.2127. PMID 25372935.
30. Keefe RS, Silva SG, Perkins DO, Lieberman JA (1 January 1999). "The effects of atypical antipsychotic drugs on neurocognitive impairment in schizophrenia: a review and meta-analysis". Schizophrenia Bulletin. 25 (2): 201–22. doi:10.1093/oxfordjournals.schbul.a033374. PMID 10416727.
31. "NICE Treatment Guidance 2014". from the original on 13 August 2014. Retrieved 7 August 2014.
32. McGorry PD, Hartmann JA, Spooner R, Nelson B (June 2018). "Beyond the "at risk mental state" concept: transitioning to transdiagnostic psychiatry". World Psychiatry. 17 (2): 133–142. doi:10.1002/wps.20514. PMC 5980504. PMID 29856558.
33. Starzer MS, Nordentoft M, Hjorthøj C (April 2018). "Rates and Predictors of Conversion to Schizophrenia or Bipolar Disorder Following Substance-Induced Psychosis". The American Journal of Psychiatry. 175 (4). American Psychiatric Association Publishing: 343–350. doi:10.1176/appi.ajp.2017.17020223. PMID 29179576.
34. Robinson DG, Gallego JA, John M, Petrides G, Hassoun Y, Zhang JP, et al. (November 2015). "A Randomized Comparison of Aripiprazole and Risperidone for the Acute Treatment of First-Episode Schizophrenia and Related Disorders: 3-Month Outcomes". Schizophrenia Bulletin. 41 (6): 1227–1236. doi:10.1093/schbul/sbv125. PMC 4601722. PMID 26338693.
35. Gómez-Revuelta M, Pelayo-Terán JM, Juncal-Ruiz M, Vázquez-Bourgon J, Suárez-Pinilla P, Romero-Jiménez R, et al. (April 2020). "Antipsychotic Treatment Effectiveness in First Episode of Psychosis: PAFIP 3-Year Follow-Up Randomized Clinical Trials Comparing Haloperidol, Olanzapine, Risperidone, Aripiprazole, Quetiapine, and Ziprasidone". The International Journal of Neuropsychopharmacology. 23 (4): 217–229. doi:10.1093/ijnp/pyaa004. PMC 7177160. PMID 31974576.
36. Leucht S, Arbter D, Engel RR, Kissling W, Davis JM (April 2009). "How effective are second-generation antipsychotic drugs? A meta-analysis of placebo-controlled trials". Molecular Psychiatry. 14 (4): 429–47. doi:10.1038/sj.mp.4002136. PMID 18180760.
37. Leucht S, Cipriani A, Spineli L, Mavridis D, Orey D, Richter F, Samara M, Barbui C, Engel RR, Geddes JR, Kissling W, Stapf MP, Lässig B, Salanti G, Davis JM (September 2013). "Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis". Lancet. 382 (9896): 951–62. doi:10.1016/S0140-6736(13)60733-3. PMID 23810019. S2CID 32085212.
38. Beitinger R, Lin J, Kissling W, Leucht S (October 2008). "Comparative remission rates of schizophrenic patients using various remission criteria". Progress in Neuro-Psychopharmacology & Biological Psychiatry. 32 (7): 1643–51. doi:10.1016/j.pnpbp.2008.06.008. PMID 18616969. S2CID 207408308.
39. Ceraso A, Lin JJ, Schneider-Thoma J, Siafis S, Tardy M, Komossa K, et al. (August 2020). "Maintenance treatment with antipsychotic drugs for schizophrenia". The Cochrane Database of Systematic Reviews. 2020 (8): CD008016. doi:10.1002/14651858.CD008016.pub3. PMC 9702459. PMID 32840872. S2CID 221306099.
40. Tiihonen J, Tanskanen A, Taipale H (August 2018). "20-Year Nationwide Follow-Up Study on Discontinuation of Antipsychotic Treatment in First-Episode Schizophrenia". The American Journal of Psychiatry. 175 (8). American Psychiatric Association Publishing: 765–773. doi:10.1176/appi.ajp.2018.17091001. PMID 29621900.
41. Kinon BJ, Ascher-Svanum H, Adams DH, Chen L (October 2008). "The temporal relationship between symptom change and treatment discontinuation in a pooled analysis of 4 schizophrenia trials". Journal of Clinical Psychopharmacology. 28 (5): 544–9. doi:10.1097/JCP.0b013e318185e74a. PMID 18794651. S2CID 203910.
42. Park SC, Choi MY, Choi J, Park E, Tchoe HJ, Suh JK, et al. (November 2018). "Comparative Efficacy and Safety of Long-acting Injectable and Oral Second-generation Antipsychotics for the Treatment of Schizophrenia: A Systematic Review and Meta-analysis". Clinical Psychopharmacology and Neuroscience. 16 (4): 361–375. doi:10.9758/cpn.2018.16.4.361. PMC 6245299. PMID 30466208.
43. "PSYCHOSIS and Schizophreniain adults: THE NICE GUIDELINE ON TREATMENT AND MANAGEMENT". p. 10.11.1.27.
44. Lambert TJ, Singh BS, Patel MX (November 2009). "Community treatment orders and antipsychotic long-acting injections". The British Journal of Psychiatry. Supplement. 52 (S52). Royal College of Psychiatrists: S57-62. doi:10.1192/bjp.195.52.s57. PMID 19880919.
45. Young LL, Kradjan WA, Guglielmo BJ, Corelli RL, Williams BR, Koda-Kimble MA (2009). Applied therapeutics: the clinical use of drugs (9th ed.). Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins. p. 3040. ISBN 978-0-7817-6555-8.
46. Correll CU, Sheridan EM, DelBello MP (March 2010). "Antipsychotic and mood stabilizer efficacy and tolerability in pediatric and adult patients with bipolar I mania: a comparative analysis of acute, randomized, placebo-controlled trials". Bipolar Disorders. 12 (2): 116–41. doi:10.1111/j.1399-5618.2010.00798.x. PMID 20402706.
47. "DailyMed - CAPLYTA- lumateperone capsule". dailymed.nlm.nih.gov. Retrieved 10 December 2022.
48. Earley W, Burgess MV, Rekeda L, Dickinson R, Szatmári B, Németh G, et al. (June 2019). "Cariprazine Treatment of Bipolar Depression: A Randomized Double-Blind Placebo-Controlled Phase 3 Study". The American Journal of Psychiatry. 176 (6): 439–448. doi:10.1176/appi.ajp.2018.18070824. PMID 30845817. S2CID 73471270.
49. Lowes R. "Lurasidone Approved for Bipolar Depression". Medscape. from the original on 2 October 2013. Retrieved 2 October 2013.
50. Tohen M, Katagiri H, Fujikoshi S, Kanba S (July 2013). "Efficacy of olanzapine monotherapy in acute bipolar depression: a pooled analysis of controlled studies". Journal of Affective Disorders. 149 (1–3): 196–201. doi:10.1016/j.jad.2013.01.022. PMID 23485111.
51. Thase ME (February 2008). "Quetiapine monotherapy for bipolar depression". Neuropsychiatric Disease and Treatment. 4 (1): 11–21. doi:10.2147/ndt.s1162. PMC 2515925. PMID 18728771.
52. Tohen M, Greil W, Calabrese JR, Sachs GS, Yatham LN, Oerlinghausen BM, et al. (July 2005). "Olanzapine versus lithium in the maintenance treatment of bipolar disorder: a 12-month, randomized, double-blind, controlled clinical trial". The American Journal of Psychiatry. 162 (7): 1281–1290. doi:10.1176/appi.ajp.162.7.1281. PMID 15994710. S2CID 20932562.
53. Duffy A, Milin R, Grof P (February 2009). "Maintenance treatment of adolescent bipolar disorder: open study of the effectiveness and tolerability of quetiapine". BMC Psychiatry. 9: 4. doi:10.1186/1471-244X-9-4. PMC 2644292. PMID 19200370.
54. Weisler RH, Nolen WA, Neijber A, Hellqvist A, Paulsson B (November 2011). "Continuation of quetiapine versus switching to placebo or lithium for maintenance treatment of bipolar I disorder (Trial 144: a randomized controlled study)". The Journal of Clinical Psychiatry. 72 (11): 1452–1464. doi:10.4088/JCP.11m06878. PMID 22054050.
55. Cipriani A, Rendell JM, Geddes J (January 2009). Cipriani A (ed.). "Olanzapine in long-term treatment for bipolar disorder". The Cochrane Database of Systematic Reviews (1): CD004367. doi:10.1002/14651858.CD004367.pub2. PMID 19160237. S2CID 205173641.
56. Lehman AF, Lieberman JA, Dixon LB, McGlashan TH, Miller AL, Perkins DO, Kreyenbuhl J (February 2004). "Practice guideline for the treatment of patients with schizophrenia, second edition". The American Journal of Psychiatry. 161 (2 Suppl): 1–56. PMID 15000267.
57. National Collaborating Centre (2009). "Schizophrenia". NCBI Bookshelf. PMID 20704054. Retrieved 9 March 2021.
58. Ventimiglia J, Kalali AH, Vahia IV, Jeste DV (November 2010). "An analysis of the intended use of atypical antipsychotics in dementia". Psychiatry. 7 (11): 14–17. PMC 3010964. PMID 21191528.
59. AMDA – The Society for Post-Acute and Long-Term Care Medicine (February 2014). "Ten Things Physicians and Patients Should Question". Choosing Wisely: an initiative of the ABIM Foundation. AMDA – The Society for Post-Acute and Long-Term Care Medicine. from the original on 13 September 2014. Retrieved 20 April 2015..
60. Ballard C, Waite J (January 2006). Ballard CG (ed.). "The effectiveness of atypical antipsychotics for the treatment of aggression and psychosis in Alzheimer's disease". The Cochrane Database of Systematic Reviews (1): CD003476. doi:10.1002/14651858.CD003476.pub2. PMID 16437455.
61. Lühnen J, Richter T, Calo S, Meyer G, Köpke S, Möhler R (August 2023). "Psychosocial interventions for reducing antipsychotic medication in care home residents". The Cochrane Database of Systematic Reviews. 2023 (8): CD008634. doi:10.1002/14651858.CD008634.pub3. PMC 10471006. PMID 37650479.
62. Komossa K, Depping AM, Gaudchau A, Kissling W, Leucht S (December 2010). "Second-generation antipsychotics for major depressive disorder and dysthymia". The Cochrane Database of Systematic Reviews (12): CD008121. doi:10.1002/14651858.CD008121.pub2. PMID 21154393.
63. Spielmans GI, Berman MI, Linardatos E, Rosenlicht NZ, Perry A, Tsai AC (2013). "Adjunctive atypical antipsychotic treatment for major depressive disorder: a meta-analysis of depression, quality of life, and safety outcomes". PLOS Medicine. 10 (3): e1001403. doi:10.1371/journal.pmed.1001403. PMC 3595214. PMID 23554581.
64. Truven Health Analytics, Inc. DrugPoint System (Internet) [cited 2013 Oct 2]. Greenwood Village, CO: Thomsen Healthcare; 2013.
65. "FDA Psychopharmacologic Drugs Advisory Committee Hearing" (PDF). American Academy of Child & Adolescent Psychiatry. Archived (PDF) from the original on 9 October 2022. Retrieved 31 May 2020.
66. Al-Wandi A, Landén M, Nordenskjöld A (6 November 2023). "Antipsychotics in the maintenance phase for psychotic depression". Acta Psychiatrica Scandinavica. 149 (1): 6–17. doi:10.1111/acps.13628. ISSN 0001-690X. PMID 37932158.
67. Hálfdánarson Ó, Zoëga H, Aagaard L, Bernardo M, Brandt L, Fusté AC, Furu K, Garuoliené K, Hoffmann F, Huybrechts KF, Kalverdijk LJ, Kawakami K, Kieler H, Kinoshita T, Litchfield M (October 2017). "International trends in antipsychotic use: A study in 16 countries, 2005-2014". European Neuropsychopharmacology. 27 (10): 1064–1076. doi:10.1016/j.euroneuro.2017.07.001. ISSN 1873-7862. PMID 28755801.
68. Radha Krishnan RP, Harrison C, Buckley N, Raubenheimer JE (April 2024). "On- and off-label utilisation of antipsychotics in Australia (2000–2021): Retrospective analysis of two medication datasets". Australian & New Zealand Journal of Psychiatry. 58 (4): 320–333. doi:10.1177/00048674231210209. ISSN 0004-8674. PMC 10960313. PMID 37941354.
69. McKean A, Monasterio E (1 May 2012). "Off-label use of atypical antipsychotics: cause for concern?". CNS Drugs. 26 (5): 383–390. doi:10.2165/11632030-000000000-00000. ISSN 1179-1934. PMID 22448598.
70. Maher AR, Theodore G (June 2012). "Summary of the comparative effectiveness review on off-label use of atypical antipsychotics". Journal of Managed Care Pharmacy. 18 (5 Suppl B): S1-20. doi:10.18553/jmcp.2012.18.s5-b.1. PMC 10438344. PMID 22784311.
71. Maglione M, Maher AR, Hu J, Wang Z, Shanman R, Shekelle PG, Roth B, Hilton L, Suttorp MJ (2011). Off-Label Use of Atypical Antipsychotics: An Update. Comparative Effectiveness Reviews, No. 43. Rockville: Agency for Healthcare Research and Quality. PMID 22973576.
72. Coe HV, Hong IS (May 2012). "Safety of low doses of quetiapine when used for insomnia". The Annals of Pharmacotherapy. 46 (5): 718–722. doi:10.1345/aph.1Q697. PMID 22510671. S2CID 9888209.
73. Pillinger T, McCutcheon RA, Vano L, Mizuno Y, Arumuham A, Hindley G, et al. (January 2020). "Comparative effects of 18 antipsychotics on metabolic function in patients with schizophrenia, predictors of metabolic dysregulation, and association with psychopathology: a systematic review and network meta-analysis". The Lancet. Psychiatry. 7 (1): 64–77. doi:10.1016/s2215-0366(19)30416-x. PMC 7029416. PMID 31860457.
74. Yoshida K, Takeuchi H (March 2021). "Dose-dependent effects of antipsychotics on efficacy and adverse effects in schizophrenia". Behavioural Brain Research. 402: 113098. doi:10.1016/j.bbr.2020.113098. PMID 33417992. S2CID 230507941.
75. De Crescenzo F, D'Alò GL, Ostinelli EG, Ciabattini M, Di Franco V, Watanabe N, et al. (July 2022). "Comparative effects of pharmacological interventions for the acute and long-term management of insomnia disorder in adults: a systematic review and network meta-analysis". Lancet. 400 (10347): 170–184. doi:10.1016/S0140-6736(22)00878-9. hdl:11380/1288245. PMID 35843245. S2CID 250536370.
76. Work Group on Borderline Personality Disorder (2001). Practice Guideline for the Treatment of Patients With Borderline Personality Disorder. American Psychiatric Association Publications. p. 4. ISBN 978-0-89042-319-6. Retrieved 5 June 2013.
77. "Antipsychotics are commonly prescribed to people with personality disorders, contrary to guidelines". NIHR Evidence. 10 November 2022. doi:10.3310/nihrevidence_54520. S2CID 253467990.
78. Hardoon S, Hayes J, Viding E, McCrory E, Walters K, Osborn D (March 2022). "Prescribing of antipsychotics among people with recorded personality disorder in primary care: a retrospective nationwide cohort study using The Health Improvement Network primary care database". BMJ Open. 12 (3): e053943. doi:10.1136/bmjopen-2021-053943. PMC 8968526. PMID 35264346.
79. Zuddas A, Zanni R, Usala T (August 2011). "Second generation antipsychotics (SGAs) for non-psychotic disorders in children and adolescents: a review of the randomized controlled studies". European Neuropsychopharmacology. 21 (8): 600–20. doi:10.1016/j.euroneuro.2011.04.001. PMID 21550212. S2CID 1254352.
80. Pringsheim T, Doja A, Gorman D, McKinlay D, Day L, Billinghurst L, Carroll A, Dion Y, Luscombe S, Steeves T, Sandor P (March 2012). "Canadian guidelines for the evidence-based treatment of tic disorders: pharmacotherapy". Canadian Journal of Psychiatry. 57 (3): 133–43. doi:10.1177/070674371205700302. PMID 22397999.
81. McPheeters ML, Warren Z, Sathe N, Bruzek JL, Krishnaswami S, Jerome RN, Veenstra-Vanderweele J (May 2011). "A systematic review of medical treatments for children with autism spectrum disorders". Pediatrics. 127 (5): e1312–21. doi:10.1542/peds.2011-0427. PMID 21464191. S2CID 2903864.
82. "Evidence Lacking to Support Many Off-label Uses of Atypical Antipsychotics" (Press release). Agency for Healthcare Research and Quality. 17 January 2007. from the original on 25 February 2013. Retrieved 29 July 2013.
83. James AC (2010). "Prescribing antipsychotics for children and adolescents". Advances in Psychiatric Treatment. 16 (1): 63–75. doi:10.1192/apt.bp.108.005652.
84. Truven Health Analytics, Inc. DRUGDEX System (Internet) [cited 2013 Oct 10]. Greenwood Village, CO: Thomsen Healthcare; 2013.
85. "Antipsychotics are increasingly prescribed to children and teenagers". NIHR Evidence. 18 April 2023. doi:10.3310/nihrevidence_57289. S2CID 258224542.
86. Radojčić MR, Pierce M, Hope H, Senior M, Taxiarchi VP, Trefan L, et al. (February 2023). "Trends in antipsychotic prescribing to children and adolescents in England: cohort study using 2000-19 primary care data". The Lancet. Psychiatry. 10 (2): 119–128. doi:10.1016/s2215-0366(22)00404-7. PMID 36638816. S2CID 255703855.
87. Romeo R, Knapp M, Tyrer P, Crawford M, Oliver-Africano P (July 2009). "The treatment of challenging behaviour in intellectual disabilities: cost-effectiveness analysis". Journal of Intellectual Disability Research. 53 (7): 633–43. doi:10.1111/j.1365-2788.2009.01180.x. PMID 19460067. S2CID 34448894.
88. Linton D, Barr AM, Honer WG, Procyshyn RM (May 2013). "Antipsychotic and psychostimulant drug combination therapy in attention deficit/hyperactivity and disruptive behavior disorders: a systematic review of efficacy and tolerability". Current Psychiatry Reports. 15 (5): 355. doi:10.1007/s11920-013-0355-6. PMID 23539465. S2CID 45484062.
89. Oh ES, Needham DM, Nikooie R, Wilson LM, Zhang A, Robinson KA, Neufeld KJ (October 2019). "Antipsychotics for Preventing Delirium in Hospitalized Adults: A Systematic Review". Annals of Internal Medicine. 171 (7): 474–484. doi:10.7326/M19-1859. PMID 31476766.
90. Kane JM, Correll CU (2010). "Pharmacologic treatment of schizophrenia". Dialogues in Clinical Neuroscience. 12 (3): 345–57. doi:10.31887/DCNS.2010.12.3/jkane. PMC 3085113. PMID 20954430.
91. Barry SJ, Gaughan TM, Hunter R (June 2012). "Schizophrenia". BMJ Clinical Evidence. 2012. PMC 3385413. PMID 23870705.
92. Schultz SH, North SW, Shields CG (June 2007). "Schizophrenia: a review". American Family Physician. 75 (12): 1821–9. CiteSeerX 10.1.1.602.7571. PMID 17619525.
93. Taylor DM, Duncan-McConnell D (2000). "Refractory schizophrenia and atypical antipsychotics". Journal of Psychopharmacology. 14 (4): 409–18. doi:10.1177/026988110001400411. PMID 11198061. S2CID 27270415.
94. Essali A, Al-Haj Haasan N, Li C, Rathbone J (January 2009). "Clozapine versus typical neuroleptic medication for schizophrenia". The Cochrane Database of Systematic Reviews. 2009 (1): CD000059. doi:10.1002/14651858.CD000059.pub2. PMC 7065592. PMID 19160174.
95. Heres S, Davis J, Maino K, Jetzinger E, Kissling W, Leucht S (February 2006). "Why olanzapine beats risperidone, risperidone beats quetiapine, and quetiapine beats olanzapine: an exploratory analysis of head-to-head comparison studies of second-generation antipsychotics". The American Journal of Psychiatry. 163 (2): 185–94. doi:10.1176/appi.ajp.163.2.185. PMID 16449469. S2CID 3849348.
96. Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO, Keefe RS, Davis SM, Davis CE, Lebowitz BD, Severe J, Hsiao JK (September 2005). "Effectiveness of antipsychotic drugs in patients with chronic schizophrenia". The New England Journal of Medicine. 353 (12): 1209–23. doi:10.1056/NEJMoa051688. PMID 16172203. S2CID 22499842.
97. Swartz MS, Stroup TS, McEvoy JP, Davis SM, Rosenheck RA, Keefe RS, Hsiao JK, Lieberman JA (May 2008). "Special Section on Implications of CATIE: What CATIE Found: Results From the Schizophrenia Trial". Psychiatric Services. 59 (5): 500–506. doi:10.1176/ps.2008.59.5.500. ISSN 1075-2730. PMC 5033643. PMID 18451005.
98. Voruganti LP, Baker LK, Awad AG (March 2008). "New generation antipsychotic drugs and compliance behaviour". Current Opinion in Psychiatry. 21 (2): 133–9. doi:10.1097/YCO.0b013e3282f52851. PMID 18332660. S2CID 34935.
99. Paczynski RP, Alexander GC, Chinchilli VM, Kruszewski SP (January 2012). "Quality of evidence in drug compendia supporting off-label use of typical and atypical antipsychotic medications". The International Journal of Risk & Safety in Medicine. 24 (3): 137–146. doi:10.3233/JRS-2012-0567. PMID 22936056.
100. Owens DC (2008). "How CATIE brought us back to Kansas: a critical re-evaluation of the concept of atypical antipsychotics and their place in the treatment of schizophrenia". Advances in Psychiatric Treatment. 14 (1): 17–28. doi:10.1192/apt.bp.107.003970.
101. Fischer-Barnicol D, Lanquillon S, Haen E, Zofel P, Koch HJ, Dose M, Klein HE (2008). "Typical and atypical antipsychotics--the misleading dichotomy. Results from the Working Group 'Drugs in Psychiatry' (AGATE)". Neuropsychobiology. 57 (1–2): 80–87. doi:10.1159/000135641. PMID 18515977. S2CID 2669203.
102. Casey DE (March 1999). "Tardive dyskinesia and atypical antipsychotic drugs". Schizophrenia Research. 35 (Suppl 1): S61–S66. doi:10.1016/S0920-9964(98)00160-1. PMID 10190226. S2CID 31807817.
103. Makhinson M (January 2010). "Biases in medication prescribing: the case of second-generation antipsychotics". Journal of Psychiatric Practice. 16 (1): 15–21. doi:10.1097/01.pra.0000367774.11260.e4. PMID 20098227. S2CID 46530288.
104. American Psychiatric Association (September 2013). "Five Things Physicians and Patients Should Question". Choosing Wisely: an initiative of the ABIM Foundation. American Psychiatric Association. from the original on 3 December 2013. Retrieved 30 December 2013., which cites
     • Practice Guideline for the Treatment of Patients With Schizophrenia. Vol. 1 (Second ed.). American Psychiatric Association. 2006. doi:10.1176/appi.books.9780890423363.45859. ISBN 978-0-89042-336-3.
     • Joint Commission (30 June 2013). "HBIPS-4, Patients discharged on multiple antipsychotic medications". Specifications Manual for Joint Commission National Quality Core Measures. from the original on 10 November 2013. Retrieved 27 October 2013.
     • Stahl SM, Grady MM (February 2004). "A critical review of atypical antipsychotic utilization: comparing monotherapy with polypharmacy and augmentation". Current Medicinal Chemistry. 11 (3): 313–27. doi:10.2174/0929867043456070. PMID 14965234.
105. Barry SJ, Gaughan TM, Hunter R (June 2012). "Schizophrenia". BMJ Clin Evid. 2012. PMC 3385413. PMID 23870705.
106. Nakata Y, Kanahara N, Iyo M (December 2017). "Dopamine supersensitivity psychosis in schizophrenia: Concepts and implications in clinical practice". Journal of Psychopharmacology. 31 (12): 1511–1518. doi:10.1177/0269881117728428. PMID 28925317. S2CID 1957881.
107. Ware MR, Feller DB, Hall KL (4 January 2018). "Neuroleptic Malignant Syndrome: Diagnosis and Management". The Primary Care Companion for CNS Disorders. 20 (1). doi:10.4088/PCC.17r02185. PMID 29325237.
108. Carbon M, Kane JM, Leucht S, Correll CU (October 2018). "Tardive dyskinesia risk with first- and second-generation antipsychotics in comparative randomized controlled trials: a meta-analysis". World Psychiatry. 17 (3): 330–340. doi:10.1002/wps.20579. PMC 6127753. PMID 30192088.
109. Moore DP, Puri BK (2012). Textbook of Clinical Neuropsychiatry and Behavioral Neuroscience, Third Edition. CRC Press. p. 791. ISBN 978-1-4441-6494-7. from the original on 25 November 2017.
110. De Berardis D, Rapini G, Olivieri L, et al. (May 2018). "Safety of antipsychotics for the treatment of schizophrenia: a focus on the adverse effects of clozapine". Therapeutic Advances in Drug Safety. 9 (5): 237–256. doi:10.1177/2042098618756261. PMC 5956953. PMID 29796248.
111. Legge SE, Walters JT (March 2019). "Genetics of clozapine-associated neutropenia: recent advances, challenges and future perspective". Pharmacogenomics. 20 (4): 279–290. doi:10.2217/pgs-2018-0188. PMC 6563116. PMID 30767710.
112. Kritharides L, Chow V, Lambert TJ (6 February 2017). "Cardiovascular disease in patients with schizophrenia". The Medical Journal of Australia. 206 (2): 91–95. doi:10.5694/mja16.00650. PMID 28152356. S2CID 5388097.
113. Sarvaiya N, Lapitskaya Y, Dima L, Manu P (August 2018). "Clozapine-Associated Pulmonary Embolism: A High-Mortality, Dose-Independent and Early-Onset Adverse Effect". American Journal of Therapeutics. 25 (4): e434–e438. doi:10.1097/MJT.0000000000000806. PMID 29985823. S2CID 51608744.
114. Teodoro T, Nogueira V, Aldeias J, Teles Martins M, Salgado J (September 2022). "Clozapine Associated Periorbital Edema in First Episode Psychosis: A Case Report of a Rare Adverse Effect in Treatment-Resistant Schizophrenia". Journal of Clinical Psychopharmacology. 42 (6): 594–596. doi:10.1097/JCP.0000000000001600. PMID 36066404. S2CID 252088054.
115. Citrome L, McEvoy JP, Saklad SR (2016). "Guide to the Management of Clozapine-Related Tolerability and Safety Concerns". Clinical Schizophrenia & Related Psychoses. 10 (3): 163–177. doi:10.3371/1935-1232.10.3.163. PMID 27732102.
116. Sriretnakumar V, Huang E, Müller DJ (2015). "Pharmacogenetics of clozapine treatment response and side-effects in schizophrenia: an update". Expert Opinion on Drug Metabolism & Toxicology. 11 (11): 1709–31. doi:10.1517/17425255.2015.1075003. PMID 26364648. S2CID 207492339.
117. Picchioni MM, Murray RM (July 2007). "Schizophrenia". BMJ. 335 (7610): 91–5. doi:10.1136/bmj.39227.616447.BE. PMC 1914490. PMID 17626963.
118. Adam RL, Sidi H, Midin M, et al. (2018). "The Role of Atypical Antipsychotics in Sexuality: Road to Recovery in Schizophrenia". Current Drug Targets. 19 (12): 1402–1411. doi:10.2174/1389450118666170502130126. PMID 28464773. S2CID 41487184.
119. Muench J, Hamer AM (March 2010). "Adverse effects of antipsychotic medications". American Family Physician. 81 (5): 617–22. PMID 20187598.
120. Lieberman JA (2004). "Managing anticholinergic side effects". Primary Care Companion to the Journal of Clinical Psychiatry. 6 (Suppl 2): 20–3. PMC 487008. PMID 16001097.
121. University of Hong Kong (6 September 2022). "Antipsychotic Use Associated With Elevated Risk of Breast Cancer".
122. Koller EA, Doraiswamy PM (July 2002). "Olanzapine-associated diabetes mellitus". Pharmacotherapy. 22 (7): 841–52. doi:10.1592/phco.22.11.841.33629. PMID 12126218. S2CID 27314943.
123. Weston-Green K, Huang XF, Deng C (February 2010). "Sensitivity of the female rat to olanzapine-induced weight gain—far from the clinic?". Schizophrenia Research. 116 (2–3): 299–300. doi:10.1016/j.schres.2009.09.034. PMID 19840894. S2CID 30384727.
124. Brunton LL, Chabner B, Knollmann BC, eds. (2011). Goodman & Gilman's The Pharmacological Basis of Therapeutics (12th ed.). New York: McGraw-Hill. ISBN 978-0-07-162442-8.
125. Weston-Green K, Huang XF, Deng C (2012). Chang AY (ed.). "Alterations to melanocortinergic, GABAergic and cannabinoid neurotransmission associated with olanzapine-induced weight gain". PLOS ONE. 7 (3): e33548. Bibcode:2012PLoSO...733548W. doi:10.1371/journal.pone.0033548. PMC 3306411. PMID 22438946.
126. Koller EA, Cross JT, Doraiswamy PM, Malozowski SN (September 2003). "Pancreatitis associated with atypical antipsychotics: from the Food and Drug Administration's MedWatch surveillance system and published reports". Pharmacotherapy. 23 (9): 1123–30. doi:10.1592/phco.23.10.1123.32759. PMID 14524644. S2CID 39945446.
127. Weinmann S, Read J, Aderhold V (August 2009). "Influence of antipsychotics on mortality in schizophrenia: systematic review". Schizophrenia Research. 113 (1): 1–11. doi:10.1016/j.schres.2009.05.018. PMID 19524406. S2CID 8143217.
128. Joukamaa M, Heliövaara M, Knekt P, Aromaa A, Raitasalo R, Lehtinen V (February 2006). "Schizophrenia, neuroleptic medication and mortality". The British Journal of Psychiatry. 188 (2): 122–7. doi:10.1192/bjp.188.2.122. PMID 16449697.
129. American Geriatrics Society 2012 Beers Criteria Update Expert Panel (April 2012). "American Geriatrics Society updated Beers Criteria for potentially inappropriate medication use in older adults". Journal of the American Geriatrics Society. 60 (4): 616–31. doi:10.1111/j.1532-5415.2012.03923.x. PMC 3571677. PMID 22376048.{{cite journal}}: CS1 maint: numeric names: authors list (link)
130. Medford N, Sierra M, Baker D, David A (2005). "Understanding and treating depersonalisation disorder". Advances in Psychiatric Treatment. 11 (2): 92–100. doi:10.1192/apt.11.2.92. from the original on 16 July 2011.
131. Patrick V, Levin E, Schleifer S (July 2005). "Antipsychotic polypharmacy: is there evidence for its use?". Journal of Psychiatric Practice. 11 (4): 248–57. doi:10.1097/00131746-200507000-00005. PMID 16041235. S2CID 43114395.
132. Ito H, Koyama A, Higuchi T (September 2005). "Polypharmacy and excessive dosing: psychiatrists' perceptions of antipsychotic drug prescription". The British Journal of Psychiatry. 187 (3): 243–7. doi:10.1192/bjp.187.3.243. PMID 16135861.
133. Leung JC, Ng DW, Chu RY, Chan EW, Huang L, Lum DH, et al. (September 2022). "Association of antipsychotic use with breast cancer: a systematic review and meta-analysis of observational studies with over 2 million individuals". Epidemiology and Psychiatric Sciences. 31: e61. doi:10.1017/S2045796022000476. PMC 9483823. PMID 36059215.
134. Vita A, De Peri L, Deste G, Sacchetti E (November 2012). "Progressive loss of cortical gray matter in schizophrenia: a meta-analysis and meta-regression of longitudinal MRI studies". Translational Psychiatry. 2 (11): e190. doi:10.1038/tp.2012.116. PMC 3565772. PMID 23168990.
135. Radua J, Borgwardt S, Crescini A, Mataix-Cols D, Meyer-Lindenberg A, McGuire PK, Fusar-Poli P (November 2012). "Multimodal meta-analysis of structural and functional brain changes in first episode psychosis and the effects of antipsychotic medication". Neuroscience and Biobehavioral Reviews. 36 (10): 2325–33. doi:10.1016/j.neubiorev.2012.07.012. PMID 22910680.
136. Dorph-Petersen KA, Pierri JN, Perel JM, Sun Z, Sampson AR, Lewis DA (September 2005). "The influence of chronic exposure to antipsychotic medications on brain size before and after tissue fixation: a comparison of haloperidol and olanzapine in macaque monkeys". Neuropsychopharmacology. 30 (9): 1649–1661. doi:10.1038/sj.npp.1300710. PMID 15756305. S2CID 205679212.
137. Parks J, Radke A, Parker G, Foti ME, Eilers R, Diamond M, et al. (September 2009). "Principles of antipsychotic prescribing for policy makers, circa 2008. Translating knowledge to promote individualized treatment". Schizophrenia Bulletin. 35 (5): 931–936. doi:10.1093/schbul/sbn019. PMC 2728806. PMID 18385207.
138. Hirose S (2003). "The causes of underdiagnosing akathisia". Schizophrenia Bulletin. 29 (3): 547–58. CiteSeerX 10.1.1.618.3326. doi:10.1093/oxfordjournals.schbul.a007027. PMID 14609248.
139. Rehse M, Bartolovic M, Baum K, Richter D, Weisbrod M, Roesch-Ely D (2016). "Influence of Antipsychotic and Anticholinergic Loads on Cognitive Functions in Patients with Schizophrenia". Schizophrenia Research and Treatment. 2016: 8213165. doi:10.1155/2016/8213165. PMC 4842070. PMID 27144021.
140. Tampi RR, Tampi DJ, Balachandran S, Srinivasan S (September 2016). "Antipsychotic use in dementia: a systematic review of benefits and risks from meta-analyses". Therapeutic Advances in Chronic Disease. 7 (5): 229–245. doi:10.1177/2040622316658463. PMC 4994396. PMID 27583123.
141. MacKenzie NE, Kowalchuk C, Agarwal SM, Costa-Dookhan KA, Caravaggio F, Gerretsen P, et al. (5 December 2018). "Antipsychotics, Metabolic Adverse Effects, and Cognitive Function in Schizophrenia". Frontiers in Psychiatry. 9: 622. doi:10.3389/fpsyt.2018.00622. PMC 6290646. PMID 30568606.
142. Mueller C, John C, Perera G, Aarsland D, Ballard C, Stewart R (January 2021). "Antipsychotic use in dementia: the relationship between neuropsychiatric symptom profiles and adverse outcomes". European Journal of Epidemiology. 36 (1): 89–101. doi:10.1007/s10654-020-00643-2. PMC 7847435. PMID 32415541.
143. Steinberg M, Lyketsos CG (September 2012). "Atypical antipsychotic use in patients with dementia: managing safety concerns". The American Journal of Psychiatry. 169 (9): 900–906. doi:10.1176/appi.ajp.2012.12030342. PMC 3516138. PMID 22952071.
144. Joint Formulary Committee B, ed. (March 2009). "4.2.1". British National Formulary (57 ed.). United Kingdom: Royal Pharmaceutical Society of Great Britain. p. 192. ISBN 978-0-85369-845-6. Withdrawal of antipsychotic drugs after long-term therapy should always be gradual and closely monitored to avoid the risk of acute withdrawal syndromes or rapid relapse.
145. Haddad P, Haddad PM, Dursun S, Deakin B (2004). Adverse Syndromes and Psychiatric Drugs: A Clinical Guide. OUP Oxford. pp. 207–216. ISBN 

April 11, 2024