What is Olanzapine?

Introduction

Olanzapine, sold under the trade name Zyprexa among others, is an atypical antipsychotic primarily used to treat schizophrenia and bipolar disorder.

For schizophrenia, it can be used for both new-onset disease and long-term maintenance. It is taken by mouth or by injection into a muscle.

Common side effects include weight gain, movement disorders, dizziness, feeling tired, constipation, and dry mouth. Other side effects include low blood pressure with standing, allergic reactions, neuroleptic malignant syndrome, high blood sugar, seizures, gynecomastia, erectile dysfunction, and tardive dyskinesia. In older people with dementia, its use increases the risk of death. Use in the later part of pregnancy may result in a movement disorder in the baby for some time after birth. Although how it works is not entirely clear, it blocks dopamine and serotonin receptors.

Brief History

Olanzapine was patented in 1971 and approved for medical use in the United States in 1996. It is available as a generic medication. In 2017, it was the 239th-most commonly prescribed medication in the United States, with more than two million prescriptions. Lilly also markets olanzapine in a fixed-dose combination with fluoxetine as olanzapine/fluoxetine (Symbyax).

Chemical Synthesis

The preparation of olanzapine was first disclosed in a series of patents from Eli Lilly & Co. in the 1990s. In the final two steps, 5-methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile was reduced with stannous chloride in ethanol to give the substituted thienobenzodiazepine ring system, and this was treated with methylpiperazine in a mixture of dimethyl sulfoxide and toluene as solvent to produce the drug.

Medical Uses

Schizophrenia

The first-line psychiatric treatment for schizophrenia is antipsychotic medication, with olanzapine being one such medication. Olanzapine appears to be effective in reducing symptoms of schizophrenia, treating acute exacerbations, and treating early-onset schizophrenia. The usefulness of maintenance therapy, however, is difficult to determine, as more than half of people in trials quit before the 6-week completion date. Treatment with olanzapine (like clozapine) may result in increased weight gain and increased glucose and cholesterol levels when compared to most other second-generation antipsychotic drugs used to treat schizophrenia.

Comparison

The UK National Institute for Health and Care Excellence (NICE), the British Association for Psychopharmacology, and the World Federation of Societies for Biological Psychiatry suggest that little difference in effectiveness is seen between antipsychotics in prevention of relapse, and recommend that the specific choice of antipsychotic be chosen based on a person’s preference and the drug’s side-effect profile. The US Agency for Healthcare Research and Quality concludes that olanzapine is not different from haloperidol in the treatment of positive symptoms and general psychopathology, or in overall assessment, but that it is superior for the treatment of negative and depressive symptoms. It has a lower risk of causing movement disorders than typical antipsychotics.

In a 2013 comparison of fifteen antipsychotic drugs in schizophrenia, olanzapine was ranked third in efficacy. It was 5% more effective than risperidone (fourth), 24-27% more effective than haloperidol, quetiapine, and aripiprazole, and 33% less effective than clozapine (first). A 2013 review of first-episode schizophrenia concluded that olanzapine is superior to haloperidol in providing a lower discontinuation rate, and in short-term symptom reduction, response rate, negative symptoms, depression, cognitive function, discontinuation due to poor efficacy, and long-term relapse, but not in positive symptoms or on the clinical global impressions (CGI) score. In contrast, pooled second-generation antipsychotics showed superiority to first-generation antipsychotics only against the discontinuation, negative symptoms (with a much larger effect seen among industry- compared to government-sponsored studies), and cognition scores. Olanzapine caused less extrapyramidal side effects and less akathisia, but caused significantly more weight gain, serum cholesterol increase, and triglyceride increase than haloperidol.

A 2012 review concluded that among ten atypical antipsychotics, only clozapine, olanzapine, and risperidone were better than first-generation antipsychotics. A 2011 review concluded that neither first- nor second-generation antipsychotics produce clinically meaningful changes in CGI scores, but found that olanzapine and amisulpride produce larger effects on the PANSS and BPRS batteries than five other second-generation antipsychotics or pooled first-generation antipsychotics. A 2010 Cochrane systematic review found that olanzapine may have a slight advantage in effectiveness when compared to aripiprazole, quetiapine, risperidone, and ziprasidone. No differences in effectiveness were detected when comparing olanzapine to amisulpride and clozapine. A 2014 meta-analysis of nine published trials having minimum duration six months and median duration 52 weeks concluded that olanzapine, quetiapine, and risperidone had better effects on cognitive function than amisulpride and haloperidol.

Bipolar Disorder

Olanzapine is recommended by NICE as a first-line therapy for the treatment of acute mania in bipolar disorder. Other recommended first-line treatments are haloperidol, quetiapine, and risperidone. It is recommended in combination with fluoxetine as a first-line therapy for acute bipolar depression, and as a second-line treatment by itself for the maintenance treatment of bipolar disorder.

The Network for Mood and Anxiety Treatments recommends olanzapine as a first-line maintenance treatment in bipolar disorder and the combination of olanzapine with fluoxetine as second-line treatment for bipolar depression.

A review on the efficacy of olanzapine as maintenance therapy in patients with bipolar disorder was published by Dando & Tohen in 2006. A 2014 meta-analysis concluded that olanzapine with fluoxetine was the most effective among nine treatments for bipolar depression included in the analysis.

Other Uses

Olanzapine may be useful in promoting weight gain in underweight adult outpatients with anorexia nervosa. However, no improvement of psychological symptoms was noted.

Olanzapine has been shown to be helpful in addressing a range of anxiety and depressive symptoms in individuals with schizophrenia and schizoaffective disorders, and has since been used in the treatment of a range of mood and anxiety disorders. Olanzapine is no less effective than lithium or valproate and more effective than placebo in treating bipolar disorder. It has also been used for Tourette syndrome and stuttering.

Olanzapine has been studied for the treatment of hyperactivity, aggressive behaviour, and repetitive behaviours in autism.

Olanzapine is frequently prescribed off-label for the treatment of insomnia, including difficulty falling asleep and staying asleep. The daytime sedation experienced with olanzapine is generally comparable to quetiapine and lurasidone, which is a frequent complaint in clinical trials. In some cases, the sedation due to olanzapine impaired the ability of people to wake up at a consistent time every day. Some evidence of efficacy for treating insomnia is seen, but long-term studies (especially for safety) are still needed.

Olanzapine has been recommended to be used in antiemetic regimens in people receiving chemotherapy that has a high risk for vomiting.

Specific Populations

Pregnancy and Lactation

Olanzapine is associated with the highest placental exposure of any atypical antipsychotic. Despite this, the available evidence suggests it is safe during pregnancy, although the evidence is insufficiently strong to say anything with a high degree of confidence. Olanzapine is associated with weight gain, which according to recent studies, may put olanzapine-treated patients’ offspring at a heightened risk for neural tube defects (e.g. spina bifida). Breastfeeding in women taking olanzapine is advised against because olanzapine is secreted in breast milk, with one study finding that the exposure to the infant is about 1.8% that of the mother.

Elderly

Citing an increased risk of stroke, in 2004, the Committee on the Safety of Medicines in the UK issued a warning that olanzapine and risperidone, both atypical antipsychotic medications, should not be given to elderly patients with dementia. In the US, olanzapine comes with a black box warning for increased risk of death in elderly patients. It is not approved for use in patients with dementia-related psychosis. A BBC investigation in June 2008 found that this advice was being widely ignored by British doctors. Evidence suggested that the elderly are more likely to experience weight gain on olanzapine compared to aripiprazole and risperidone.

Adverse Effects

Refer to Adverse Effects of Olanzapine.

The principal side effect of olanzapine is weight gain, which may be profound in some cases and/or associated with derangement in blood-lipid and blood-sugar profiles (see section metabolic effects). A 2013 meta-analysis of the efficacy and tolerance of 15 antipsychotic drugs (APDs) found that it had the highest propensity for causing weight gain out of the 15 APDs compared with an SMD of 0.74. Extrapyramidal side effects, although potentially serious, are infrequent to rare from olanzapine, but may include tremors and muscle rigidity.

It is not recommended to be used by IM injection in acute myocardial infarction, bradycardia, recent heart surgery, severe hypotension, sick sinus syndrome, and unstable angina.

Several patient groups are at a heightened risk of side effects from olanzapine and antipsychotics in general. Olanzapine may produce nontrivial high blood sugar in people with diabetes mellitus. Likewise, the elderly are at a greater risk of falls and accidental injury. Young males appear to be at heightened risk of dystonic reactions, although these are relatively rare with olanzapine. Most antipsychotics, including olanzapine, may disrupt the body’s natural thermoregulatory systems, thus permitting excursions to dangerous levels when situations (exposure to heat, strenuous exercise) occur.

Other side effects include galactorrhoea, amenorrhea, gynecomastia, and erectile dysfunction (impotence).

Paradoxical Effects

Olanzapine is used therapeutically to treat serious mental illness. Occasionally, it can have the opposite effect and provoke serious paradoxical reactions in a small subgroup of people, causing unusual changes in personality, thoughts, or behaviour; hallucinations and excessive thoughts about suicide have also been linked to olanzapine use.

Drug-Induced OCD

Many different types of medication can create or induce pure obsessive-compulsive disorder (OCD) in patients who have never had symptoms before. A new chapter about OCD in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (2013) now specifically includes drug-induced OCD.

Atypical antipsychotics (second-generation antipsychotics), such as olanzapine (Zyprexa), have been proven to induce de novo OCD in patients.

Metabolic Effects

The US Food and Drug Administration (FDA) requires all atypical antipsychotics to include a warning about the risk of developing hyperglycaemia and diabetes, both of which are factors in the metabolic syndrome. These effects may be related to the drugs’ ability to induce weight gain, although some reports have been made of metabolic changes in the absence of weight gain. Studies have indicated that olanzapine carries a greater risk of causing and exacerbating diabetes than another commonly prescribed atypical antipsychotic, risperidone. Of all the atypical antipsychotics, olanzapine is one of the most likely to induce weight gain based on various measures. The effect is dose dependent in humans and animal models of olanzapine-induced metabolic side effects. There are some case reports of olanzapine-induced diabetic ketoacidosis. Olanzapine may decrease insulin sensitivity, though one 3-week study seems to refute this. It may also increase triglyceride levels.

Despite weight gain, a large multicentre, randomised National Institute of Mental Health study found that olanzapine was better at controlling symptoms because patients were more likely to remain on olanzapine than the other drugs. One small, open-label, nonrandomised study suggests that taking olanzapine by orally dissolving tablets may induce less weight gain, but this has not been substantiated in a blinded experimental setting.

Post-Injection Delirium/Sedation Syndrome

Postinjection delirium/sedation syndrome (PDSS) is a rare syndrome that is specific to the long-acting injectable formulation of olanzapine, olanzapine pamoate. The incidence of PDSS with olanzapine pamoate is estimated to be 0.07% of administrations, and is unique among other second-generation, long-acting antipsychotics (e.g. paliperidone palmitate), which do not appear to carry the same risk.[70] PDSS is characterised by symptoms of delirium (e.g. confusion, difficulty speaking, and uncoordinated movements) and sedation. Most people with PDSS exhibit both delirium and sedation (83%). Although less specific to PDSS, a majority of cases (67%) involved a feeling of general discomfort. PDSS may occur due to accidental injection and absorption of olanzapine pamoate into the bloodstream, where it can act more rapidly, as opposed to slowly distributing out from muscle tissue. Using the proper, intramuscular-injection technique for olanzapine pamoate helps to decrease the risk of PDSS, though it does not eliminate it entirely. This is why the FDA advises that people who are injected with olanzapine pamoate be watched for 3 hours after administration, in the event that PDSS occurs.

Animal Toxicology

Olanzapine has demonstrated carcinogenic effects in multiple studies when exposed chronically to female mice and rats, but not male mice and rats. The tumours found were in either the liver or mammary glands of the animals.

Discontinuation

The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotics to avoid acute withdrawal syndrome or rapid relapse. Symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite. Other symptoms may include restlessness, increased sweating, and trouble sleeping. Less commonly, vertigo, numbness, or muscle pains may occur. Symptoms generally resolve after a short time.

Tentative evidence indicates that discontinuation of antipsychotics can result in psychosis. It may also result in reoccurrence of the condition that is being treated. Rarely, tardive dyskinesia can occur when the medication is stopped.

Overdose

Symptoms of an overdose include tachycardia, agitation, dysarthria, decreased consciousness, and coma. Death has been reported after an acute overdose of 450 mg, but also survival after an acute overdose of 2000 mg. Fatalities generally have occurred with olanzapine plasma concentrations greater than 1000 ng/mL post mortem, with concentrations up to 5200 ng/mL recorded (though this might represent confounding by dead tissue, which may release olanzapine into the blood upon death). No specific antidote for olanzapine overdose is known, and even physicians are recommended to call a certified poison control centre for information on the treatment of such a case. Olanzapine is considered moderately toxic in overdose, more toxic than quetiapine, aripiprazole, and the SSRIs, and less toxic than the monoamine oxidase inhibitors and tricyclic antidepressants.

Interactions

Drugs or agents that increase the activity of the enzyme CYP1A2, notably tobacco smoke, may significantly increase hepatic first-pass clearance of olanzapine; conversely, drugs that inhibit CYP1A2 activity (examples: ciprofloxacin, fluvoxamine) may reduce olanzapine clearance. Carbamazepine, a known enzyme inducer, has decreased the concentration/dose ration of olanzapine by 33% compared to olanzapine alone. Another enzyme inducer, ritonavir, has also been shown to decrease the body’s exposure to olanzapine, due to its induction of the enzymes CYP1A2 and uridine 5′-diphospho-glucuronosyltransferase (UGT). Probenecid increases the total exposure (area under the curve) and maximum plasma concentration of olanzapine. Although olanzapine’s metabolism includes the minor metabolic pathway of CYP2D6, the presence of the CYP2D6 inhibitor fluoxetine does not have a clinically significant effect on olanzapine’s clearance.

Pharmacology

Pharmacodynamics

Olanzapine has a higher affinity for 5-HT2A serotonin receptors than D2 dopamine receptors, which is a common property of most atypical antipsychotics, aside from the benzamide antipsychotics such as amisulpride along with the nonbenzamides aripiprazole, brexpiprazole, blonanserin, cariprazine, melperone, and perospirone.

Olanzapine had the highest affinity of any second-generation antipsychotic towards the P-glycoprotein in one in vitro study. P-glycoprotein transports a myriad of drugs across a number of different biological membranes (found in numerous body systems) including the blood-brain barrier (a semipermeable membrane that filters the contents of blood prior to it reaching the brain); P-GP inhibition could mean that less brain exposure to olanzapine results from this interaction with the P-glycoprotein. A relatively large quantity of commonly encountered foods and medications inhibit P-GP, and pharmaceuticals fairly commonly are either substrates of P-GP, or inhibit its action; both substrates and inhibitors of P-GP effectively increase the permeability of the blood-brain barrier to P-GP substrates and subsequently increase the central activity of the substrate, while reducing the local effects on the GI tract. The mediation of olanzapine in the central nervous system by P-GP means that any other substance or drug that interacts with P-GP increases the risk for toxic accumulations of both olanzapine and the other drug.

Olanzapine is a potent antagonist of the muscarinic M3 receptor, which may underlie its diabetogenic side effects. Additionally, it also exhibits a relatively low affinity for serotonin 5-HT1, GABAA, beta-adrenergic receptors, and benzodiazepine binding sites.

The mode of action of olanzapine’s antipsychotic activity is unknown. It may involve antagonism of dopamine and serotonin receptors. Antagonism of dopamine receptors is associated with extrapyramidal effects such as tardive dyskinesia (TD), and with therapeutic effects. Antagonism of muscarinic acetylcholine receptors is associated with anticholinergic side effects such as dry mouth and constipation; in addition, it may suppress or reduce the emergence of extrapyramidal effects for the duration of treatment, but it offers no protection against the development of TD. In common with other second-generation (atypical) antipsychotics, olanzapine poses a relatively low risk of extrapyramidal side effects including TD, due to its higher affinity for the 5HT2A receptor over the D2 receptor.

Antagonizing H1 histamine receptors causes sedation and may cause weight gain, although antagonistic actions at serotonin 5-HT2C and dopamine D2 receptors have also been associated with weight gain and appetite stimulation.

Pharmacokinetics

Metabolism

Olanzapine is metabolized by the cytochrome P450 (CYP) system; principally by isozyme 1A2 (CYP1A2) and to a lesser extent by CYP2D6. By these mechanisms, more than 40% of the oral dose, on average, is removed by the hepatic first-pass effect. Clearance of olanzapine appears to vary by sex; women have roughly 25% lower clearance than men. Clearance of olanzapine also varies by race; in self-identified African Americans or Blacks, olanzapine’s clearance was 26% higher. A difference in the clearance does not apparent between individuals identifying as Caucasian, Chinese, or Japanese. Routine, pharmacokinetic monitoring of olanzapine plasma levels is generally unwarranted, though unusual circumstances (e.g. the presence of drug-drug interactions) or a desire to determine if patients are taking their medicine may prompt its use.

Chemistry

Olanzapine is unusual in having four well-characterised crystalline polymorphs and many hydrated forms.

Society and Culture

Regulatory Status

Olanzapine is approved by the US FDA for:

  • Treatment – in combination with fluoxetine – of depressive episodes associated with bipolar disorder (December 2003).
  • Long-term treatment of bipolar I disorder (January 2004).
  • Long-term treatment – in combination with fluoxetine – of resistant depression (March 2009).
  • Oral formulation: acute and maintenance treatment of schizophrenia in adults, acute treatment of manic or mixed episodes associated with bipolar I disorder (monotherapy and in combination with lithium or sodium valproate).
  • Intramuscular formulation: acute agitation associated with schizophrenia and bipolar I mania in adults.
  • Oral formulation combined with fluoxetine: treatment of acute depressive episodes associated with bipolar I disorder in adults, or treatment of acute, resistant depression in adults.
  • Treatment of the manifestations of psychotic disorders (September 1996 to March 2000).
  • Short-term treatment of acute manic episodes associated with bipolar I disorder (March 2000).
  • Short-term treatment of schizophrenia instead of the management of the manifestations of psychotic disorders (March 2000).
  • Maintaining treatment response in schizophrenic patients who had been stable for about eight weeks and were then followed for a period of up to eight months (November 2000).

The drug became generic in 2011.

Sales of Zyprexa in 2008 were $2.2 billion in the US and $4.7 billion worldwide.

Controversy and Litigation

Eli Lilly has faced many lawsuits from people who claimed they developed diabetes or other diseases after taking Zyprexa, as well as by various governmental entities, insurance companies, and others. Lilly produced a large number of documents as part of the discovery phase of this litigation, which started in 2004; the documents were ruled to be confidential by a judge and placed under seal, and later themselves became the subject of litigation.

In 2006, Lilly paid $700 million to settle around 8,000 of these lawsuits, and in early 2007, Lilly settled around 18,000 suits for $500 million, which brought the total Lilly had paid to settle suits related to the drug to $1.2 billion.

A December 2006 New York Times article based on leaked company documents concluded that the company had engaged in a deliberate effort to downplay olanzapine’s side effects. The company denied these allegations and stated that the article had been based on cherry-picked documents. The documents were provided to the Times by Jim Gottstein, a lawyer who represented mentally ill patients, who obtained them from a doctor, David Egilman, who was serving as an expert consultant on the case. After the documents were leaked to online peer-to-peer, file-sharing networks by Will Hall and others in the psychiatric survivors movement, who obtained copies, in 2007 Lilly filed a protection order to stop the dissemination of some of the documents, which Judge Jack B. Weinstein of the Brooklyn Federal District Court granted. Judge Weinstein also criticized the New York Times reporter, Gottstein, and Egilman in the ruling. The Times of London also received the documents and reported that as early as 1998, Lilly considered the risk of drug-induced obesity to be a “top threat” to Zyprexa sales. On 09 October 2000, senior Lilly research physician Robert Baker noted that an academic advisory board to which he belonged was “quite impressed by the magnitude of weight gain on olanzapine and implications for glucose.”

Lilly had threatened Egilman with criminal contempt charges regarding the documents he took and provided to reporters; in September 2007, he agreed to pay Lilly $100,000 in return for the company’s agreement to drop the threat of charges.

In September 2008, Judge Weinstein issued an order to make public Lilly’s internal documents about the drug in a different suit brought by insurance companies, pension funds, and other payors.

In March 2008, Lilly settled a suit with the state of Alaska, and in October 2008, Lilly agreed to pay $62 million to 32 states and the District of Columbia to settle suits brought under state consumer protection laws.

In 2009, Eli Lilly pleaded guilty to a US federal criminal misdemeanour charge of illegally marketing Zyprexa for off-label use and agreed to pay $1.4 billion. The settlement announcement stated “Eli Lilly admits that between September 1999 and 31 March 2001, the company promoted Zyprexa in elderly populations as treatment for dementia, including Alzheimer’s dementia. Eli Lilly has agreed to pay a $515 million criminal fine and to forfeit an additional $100 million in assets.”

Trade Names

Olanzapine is generic and available under many trade names worldwide.

Dosage Forms

Olanzapine is marketed in a number of countries, with tablets ranging from 2.5 to 20 mg. Zyprexa (and generic olanzapine) is available as an orally disintegrating “wafer”, which rapidly dissolves in saliva. It is also available in 10-mg vials for intramuscular injection.

Research

Olanzapine has been studied as an antiemetic, particularly for the control of chemotherapy-induced nausea and vomiting (CINV).

In general, olanzapine appears to be about as effective as aprepitant for the prevention of CINV, though some concerns remain for its use in this population. For example, concomitant use of metoclopramide or haloperidol increases the risk for extrapyramidal symptoms. Otherwise, olanzapine appears to be fairly well tolerated for this indication, with somnolence being the most common side effect.

Olanzapine has been considered as part of an early psychosis approach for schizophrenia. The Prevention through Risk Identification, Management, and Education study, funded by the National Institute of Mental Health and Eli Lilly, tested the hypothesis that olanzapine might prevent the onset of psychosis in people at very high risk for schizophrenia. The study examined 60 patients with prodromal schizophrenia, who were at an estimated risk of 36-54% of developing schizophrenia within a year, and treated half with olanzapine and half with placebo. In this study, patients receiving olanzapine did not have a significantly lower risk of progressing to psychosis. Olanzapine was effective for treating the prodromal symptoms, but was associated with significant weight gain.

What is Loxapine?

Introduction

Loxapine, sold under the brand names Loxitane and Adasuve (inhalation only) among others, is a typical antipsychotic medication used primarily in the treatment of schizophrenia.

The drug is a member of the dibenzoxazepine class and structurally related to clozapine. Several researchers have argued that loxapine may behave as an atypical antipsychotic.

Loxapine may be metabolised by N-demethylation to amoxapine, a tricyclic antidepressant.

Medical Uses

The US Food and Drug Administration (FDA) has approved loxapine inhalation powder for the acute treatment of agitation associated with schizophrenia or bipolar I disorder in adults.

A brief review of loxapine found no conclusive evidence that it was particularly effective in patients with paranoid schizophrenia. A subsequent systematic review considered that the limited evidence did not indicate a clear difference in its effects from other antipsychotics.

Available Forms

Loxapine can be taken by mouth as a capsule or a liquid oral concentrate. It is also available as an intramuscular injection and as a powder for inhalation.

Side Effects

Loxapine can cause side effects that are generally similar to that of other medications in the typical antipsychotic class of medications. These include, e.g. gastrointestinal problems (like constipation and abdominal pain), cardiovascular problems (like tachycardia), moderate likelihood of drowsiness (relative to other antipsychotics), and movement problems (i.e. extrapyramidal symptoms (EPS)). At lower dosages its propensity for causing EPS appears to be similar to that of atypical antipsychotics. Although it is structurally similar to clozapine, it does not have the same risk of agranulocytosis (which, even with clozapine, is less than 1%); however, mild and temporary fluctuations in blood leukocyte levels can occur. Abuse of loxapine has been reported.

The inhaled formulation of loxapine carries a low risk for a type of airway adverse reaction called bronchospasm that is not thought to occur when loxapine is taken by mouth.

Pharmacology

Mechanism of Action

Loxapine is a “mid-potency” typical antipsychotic. However, unlike most other typical antipsychotics, it has significant potency at the 5HT2A receptor (6.6 nM), which is similar to atypical antipsychotics like clozapine (5.35 nM). The higher likelihood of EPS with loxapine, compared to clozapine, may be due to its high potency for the D2 receptor.

Pharmacokinetics

Loxapine is metabolised to amoxapine, as well as its 8-hydroxy metabolite (8-hydroxyloxapine). Amoxapine is further metabolized to its 8-hydroxy metabolite (8-hydroxyamoxapine), which is also found in the blood of people taking loxapine. At steady-state after taking loxapine by mouth, the relative amounts of loxapine and its metabolites in the blood is as follows: 8-hydroxyloxapine > 8-hydroxyamoxapine > loxapine.

The pharmacokinetics of loxapine change depending on how it is given. Intramuscular injections of loxapine lead to higher blood levels and area under the curve of loxapine than when it is taken by mouth.

Chemistry

Loxapine is a dibenzoxazepine and is structurally related to clozapine.

What is Quetiapine?

Introduction

Quetiapine, sold under the brand name Seroquel among others, is an atypical antipsychotic medication used for the treatment of schizophrenia, bipolar disorder, and major depressive disorder. Despite being widely used as a sleep aid due its sedating effect, the benefits of such use do not appear to generally outweigh the side effects. It is taken by mouth.

Common side effects include sleepiness, constipation, weight gain, and dry mouth. Other side effects include low blood pressure with standing, seizures, a prolonged erection, high blood sugar, tardive dyskinesia, and neuroleptic malignant syndrome. In older people with dementia, its use increases the risk of death. Use in the third trimester of pregnancy may result in a movement disorder in the baby for some time after birth. Quetiapine is believed to work by blocking a number of receptors including serotonin and dopamine.

Quetiapine was developed in 1985 and approved for medical use in the United States in 1997. It is available as a generic medication. In 2018, it was the 59th most commonly prescribed medication in the United States, with more than 12 million prescriptions.

Brief History

AstraZeneca submitted a new drug application for a sustained-release version of quetiapine in the United States, Canada, and the European Union in the second half of 2006 for treatment of schizophrenia. AstraZeneca was to retain the exclusive right to market sustained-release quetiapine until 2017. The sustained-release quetiapine is marketed mainly as Seroquel XR. Other marketing names are Seroquel Prolong, Seroquel Depot and Seroquel XL

On 18 May 2007, AstraZeneca announced that the US Food and Drug Administration (FDA) had approved Seroquel XR for acute treatment of schizophrenia. During its 2007 Q2 earnings conference, AstraZeneca announced plans to launch Seroquel XR in the US during August 2007. However, Seroquel XR has become available in US pharmacies only after the FDA had approved Seroquel XR for use as maintenance treatment for schizophrenia, in addition to acute treatment of the illness, on 16 November 2007. The company has not provided a reason for the delay of Seroquel XR’s launch.

Health Canada approved sale of Seroquel XR on 27 September 2007.

In early October 2008, the FDA approved Seroquel XR for the treatment of bipolar depression and bipolar mania. According to AstraZeneca, Seroquel XR is “the first medication approved by the FDA for the once-daily acute treatment of both depressive and manic episodes associated with bipolar.”

On 31 July, 2008, Handa Pharmaceuticals, based in Fremont, California, announced that its abbreviated new drug application (“ANDA”) for quetiapine fumarate extended-release tablets, the generic version of AstraZeneca’s SEROQUEL XR, has been accepted by the FDA.

On 01 December 2008, Biovail announced that the FDA had accepted the company’s ANDA to market its own version of sustained-release quetiapine. Biovail’s sustained-release tablets will compete with AstraZeneca’s Seroquel XR.

On 24 December 2008, AstraZeneca notified shareholders that the FDA had asked for additional information on the company’s application to expand the use of sustained-release quetiapine for treatment of depression.

Medical Uses

Quetiapine is primarily used to treat schizophrenia or bipolar disorder. Quetiapine targets both positive and negative symptoms of schizophrenia.

Schizophrenia

In a 2013 comparison of 15 antipsychotics in effectiveness in treating schizophrenia, quetiapine demonstrated standard effectiveness. It was 13-16% more effective than ziprasidone, chlorpromazine, and asenapine and approximately as effective as haloperidol and aripiprazole.

There is tentative evidence of the benefit of quetiapine versus placebo in schizophrenia; however, definitive conclusions are not possible due to the high rate of attrition in trials (greater than 50%) and the lack of data on economic outcomes, social functioning, or quality of life.

It is debatable whether, as a class, typical or atypical antipsychotics are more effective. Both have equal drop-out and symptom relapse rates when typicals are used at low to moderate dosages. While quetiapine has lower rates of extrapyramidal side effects, there is greater sleepiness and rates of dry mouth.

A Cochrane review comparing quetiapine to other atypical antipsychotic agents tentatively concluded that it may be less efficacious than olanzapine and risperidone; produce fewer movement related side effects than paliperidone, aripiprazole, ziprasidone, risperidone and olanzapine; and produce weight gain similar to risperidone, clozapine and aripiprazole. They concluded that it produces suicide attempt, suicide; death; QTc prolongation, low blood pressure; tachycardia; sedation; gynaecomastia; galactorrhoea, menstrual irregularity and white blood cell count at a rate similar to first generation antipsychotics.

Bipolar Disorder

In those with bipolar disorder, quetiapine is used to treat depressive episodes; acute manic episodes associated with bipolar I disorder (as either monotherapy or adjunct therapy to lithium; valproate or lamotrigine); acute mixed episodes; and maintenance treatment of bipolar I disorder (as adjunct therapy to lithium or divalproex).

Major Depressive Disorder

Quetiapine is effective when used by itself and when used along with other medications in major depressive disorder (MDD). However, sedation is often an undesirable side effect.

In the United States, the United Kingdom and Australia (while not subsidised by the Australian Pharmaceutical Benefits Scheme for treatment of MDD), quetiapine is licensed for use as an add-on treatment in MDD.

Alzheimer’s Disease

Quetiapine does not decrease agitation among people with Alzheimer’s. Quetiapine worsens intellectual functioning in the elderly with dementia and therefore is not recommended.

Others

The use of low doses of quetiapine for insomnia, while common, is not recommended; there is little evidence of benefit and concerns regarding adverse effects.

It is sometimes used off-label, often as an augmentation agent, to treat conditions such as Tourette syndrome, musical hallucinations and anxiety disorders.

Quetiapine and clozapine are the most widely used medications for the treatment of Parkinson’s disease psychosis due to their very low extrapyramidal side-effect liability. Owing to the risks associated with clozapine (e.g. agranulocytosis, diabetes mellitus, etc.), clinicians often attempt treatment with quetiapine first, although the evidence to support quetiapine’s use for this indication is significantly weaker than that of clozapine.

Adverse Effects

  • Very common (>10% incidence) adverse effects:
    • Dry mouth.
    • Dizziness.
    • Headache.
    • Somnolence:
      • Drowsiness; of 15 antipsychotics quetiapine causes the 5th most sedation.
      • Extended release (XR) formulations tend to produce less sedation, dose-by-dose than the immediate release formulations.
  • Common (1–10% incidence) adverse effects:
    • High blood pressure.
    • Orthostatic hypotension.
    • High pulse rate.
    • High blood cholesterol.
    • Elevated serum triglycerides.
    • Abdominal pain.
    • Constipation.
    • Increased appetite.
    • Vomiting.
    • Increased liver enzymes.
    • Backache.
    • Asthenia.
    • Insomnia.
    • Lethargy.
    • Tremor.
    • Agitation.
    • Nasal congestion.
    • Pharyngitis.
    • Fatigue.
    • Pain.
    • Dyspepsia (Indigestion).
    • Peripheral oedema.
    • Dysphagia.
    • Extrapyramidal disease:
      • Quetiapine and clozapine are noted for their relative lack of extrapyramidal side effects.
    • Weight gain:
      • SMD 0.43 kg when compared to placebo. Produces roughly as much weight gain as risperidone, less weight gain than clozapine, olanzapine and zotepine and more weight gain than ziprasidone, lurasidone, aripiprazole and asenapine.
      • As with many other atypical antipsychotics, this action is likely due to its actions at the H1 histamine receptor and 5-HT2C receptor.
  • Rare (<1% incidence) adverse effects:
    • Prolonged QT interval.
    • Sudden cardiac death.
    • Syncope.
    • Diabetic ketoacidosis.
    • Restless legs syndrome.
    • Hyponatraemia, low blood sodium.
    • Jaundice, yellowing of the eyes, skin and mucous membranes due to an impaired ability of the body to clear bilirubin, a by product of haem breakdown.
    • Pancreatitis, pancreas swelling.
    • Agranulocytosis, a potentially fatal drop in white blood cell count.
    • Leukopenia, a drop in white blood cell count, not as severe as agranulocytosis.
    • Neutropenia, a drop in neutrophils, the cell of the immune cells that defends the body against bacterial infections.
    • Eosinophilia.
    • Anaphylaxis, a potentially fatal allergic reaction.
    • Seizure.
    • Hypothyroidism, underactive thyroid gland.
    • Myocarditis, swelling of the myocardium.
    • Cardiomyopathy.
    • Hepatitis, swelling of the liver.
    • Suicidal ideation.
    • Priapism:
      • A prolonged and painful erection.
    • Stevens-Johnson syndrome:
      • A potentially fatal skin reaction.
    • Neuroleptic malignant syndrome:
      • A rare and potentially fatal complication of antipsychotic drug treatment.
      • It is characterised by the following symptoms: tremor, rigidity, hyperthermia, tachycardia, mental status changes (e.g. confusion), etc.
    • Tardive Dyskinesia:
      • A rare and often irreversible neurological condition characterised by involuntary movements of the face, tongue, lips and rest of the body.
      • Most commonly occurs after prolonged treatment with antipsychotics.
      • It is believed to be particularly uncommon with atypical antipsychotics, especially quetiapine and clozapine

Both typical and atypical antipsychotics can cause tardive dyskinesia. According to one study, rates are lower with the atypicals at 3.9% as opposed to the typicals at 5.5%. Although quetiapine and clozapine are atypical antipsychotics, switching to these atypicals is an option to minimise symptoms of tardive dyskinesia caused by other atypicals.

Weight gain can be a problem for some, with quetiapine causing more weight gain than fluphenazine, haloperidol, loxapine, molindone, olanzapine, pimozide, risperidone, thioridazine, thiothixene, trifluoperazine, and ziprasidone, but less than chlorpromazine, clozapine, perphenazine, and sertindole.

As with some other anti-psychotics, quetiapine may lower the seizure threshold, and should be taken with caution in combination with drugs such as bupropion.

Discontinuation

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

There is tentative evidence that discontinuation of antipsychotics can result in psychosis. It may also result in reoccurrence of the condition that is being treated. Rarely tardive dyskinesia can occur when the medication is stopped.

Pregnancy and Lactation

Placental exposure is least for quetiapine compared to other atypical antipsychotics. The evidence is insufficient to rule out any risk to the foetus but available data suggests it is unlikely to result in any major foetal malformations. It is secreted in breast milk and hence quetiapine-treated mothers are advised not to breastfeed.

Abuse Potential

In contrast to most other antipsychotic drugs, which tend to be somewhat aversive and often show problems with patient compliance with prescribed medication regimes, quetiapine is sometimes associated with drug misuse and abuse potential, for its hypnotic and sedative effects. It has a limited potential for misuse, usually only in individuals with a history of polysubstance abuse and/or mental illness, and especially in those incarcerated in prisons or secure psychiatric facilities where access to alternative intoxicants is more limited. To a significantly greater extent than other atypical antipsychotic drugs, quetiapine was found to be associated with drug-seeking behaviours, and to have standardised street prices and slang terms associated with it, either by itself or in combination with other drugs (such as “Q-ball” for the intravenous injection of quetiapine mixed with cocaine). The pharmacological basis for this distinction from other second generation antipsychotic drugs is unclear, though it has been suggested that quetiapine’s comparatively lower dopamine receptor affinity and strong antihistamine activity might mean it could be regarded as more similar to sedating antihistamines in this context. While these issues have not been regarded as sufficient cause for placing quetiapine under increased legal controls, prescribers have been urged to show caution when prescribing quetiapine to individuals with characteristics that might place them at increased risk for drug misuse.

Overdose

Most instances of acute overdosage result in only sedation, hypotension and tachycardia, but cardiac arrhythmia, coma and death have occurred in adults. Serum or plasma quetiapine concentrations are usually in the 1-10 mg/L range in overdose survivors, while postmortem blood levels of 10-25 mg/L are generally observed in fatal cases. Non-toxic levels in postmortem blood extend to around 0.8 mg/kg, but toxic levels in postmortem blood can begin at 0.35 mg/kg.

Pharmacology

Pharmacodynamics

Quetiapine has the following pharmacological actions:

  • Dopamine D1, D2, D3, D4, and D5 receptor antagonist.
  • Serotonin 5-HT1A receptor partial agonist, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT3, 5-HT6, and 5-HT7 receptor antagonist, and 5-HT1B, 5-HT1D, 5-HT1E, and 5-HT1F receptor ligand.
  • α1- and α2-adrenergic receptor antagonist.
  • Histamine H1 receptor antagonist.
  • Muscarinic acetylcholine receptor antagonist.

This means quetiapine is a dopamine, serotonin, and adrenergic antagonist, and a potent antihistamine with some anticholinergic properties. Quetiapine binds strongly to serotonin receptors; the drug acts as partial agonist at 5-HT1A receptors. Serial PET scans evaluating the D2 receptor occupancy of quetiapine have demonstrated that quetiapine very rapidly disassociates from the D2 receptor. Theoretically, this allows for normal physiological surges of dopamine to elicit normal effects in areas such as the nigrostriatal and tuberoinfundibular pathways, thus minimising the risk of side-effects such as pseudo-parkinsonism as well as elevations in prolactin. Some of the antagonised receptors (serotonin, norepinephrine) are actually autoreceptors whose blockade tends to increase the release of neurotransmitters.

At very low doses, quetiapine acts primarily as a histamine receptor blocker (antihistamine) and α1-adrenergic blocker. When the dose is increased, quetiapine activates the adrenergic system and binds strongly to serotonin receptors and autoreceptors. At high doses, quetiapine starts blocking significant amounts of dopamine receptors. Off-label prescriptions, e.g. for chronic insomnia, of low-dose quetiapine is not recommended due to the harmful side-effects.

When treating schizophrenia, antagonism of D2 receptor by quetiapine in the mesolimbic pathway relieves positive symptoms and antagonism of the 5HT2A receptor in the frontal cortex of the brain relieves negative symptoms. Quetiapine has fewer extrapyramidal side effects and is less likely to cause hyperprolactinemia when compared to other drugs used to treat schizophrenia, so is used as a first line treatment.

Pharmacokinetics

Peak levels of quetiapine occur 1.5 hours after a dose. The plasma protein binding of quetiapine is 83%. The major active metabolite of quetiapine is norquetiapine (N-desalkylquetiapine). Quetiapine has an elimination half-life of 6 or 7 hours. Its metabolite, norquetiapine, has a half-life of 9 to 12 hours. Quetiapine is excreted primarily via the kidneys (73%) and in faeces (20%) after hepatic metabolism, the remainder (1%) is excreted as the drug in its unmetabolised form.

Chemistry

Quetiapine is a tetracyclic compound and is closely related structurally to clozapine, olanzapine, loxapine, and other tetracyclic antipsychotics.

Synthesis

The synthesis of quetiapine begins with a dibenzothiazepinone. The lactam is first treated with phosphoryl chloride to produce a dibenzothiazepine. A nucleophilic substitution is used to introduce the sidechain.

Society and Culture

Regulatory Status

In the United States, the FDA has approved quetiapine for the treatment of schizophrenia and of acute manic episodes associated with bipolar disorder (bipolar mania) and for treatment of bipolar depression. In 2009, quetiapine XR was approved as adjunctive treatment of major depressive disorder.

Quetiapine received its initial indication from the FDA for treatment of schizophrenia in 1997. In 2004, it received its second indication for the treatment of mania-associated bipolar disorder. In 2007 and 2008, studies were conducted on quetiapine’s efficacy in treating generalized anxiety disorder and major depression.

Patent protection for the product ended in 2012; however, in a number of regions, the long-acting version remained under patent until 2017.

Lawsuits

In April 2010, the US Department of Justice fined Astra-Zeneca $520 million for the company’s aggressive marketing of Seroquel for off-label uses. According to the Department of Justice, “the company recruited doctors to serve as authors of articles that were ghostwritten by medical literature companies and about studies the doctors in question did not conduct. AstraZeneca then used those studies and articles as the basis for promotional messages about unapproved uses of Seroquel.”

Multiple lawsuits have been filed in relation to quetiapine’s side-effects, in particular, diabetes.

Approximately 10,000 lawsuits have been filed against AstraZeneca, alleging that quetiapine caused problems ranging from slurred speech and chronic insomnia to deaths.

Controversy

In 2004, a young man named Dan Markingson committed suicide in a controversial Seroquel clinical trial at the University of Minnesota while under an involuntary commitment order. A group of University of Minnesota bioethicists charged that the trial involved an alarming number of ethical violations.

Nurofen Plus Tampering Case

In August 2011, the UK’s Medicines and Healthcare products Regulatory Agency (MHRA) issued a class-4 drug alert following reports that some batches of Nurofen plus contained Seroquel XL tablets instead.

Following the issue of the Class-4 Drug Alert, Reckitt Benckiser (UK) Ltd received further reports of rogue blister strips in cartons of two additional batches of Nurofen Plus tablets. One of the new batches contained Seroquel XL 50 mg tablets and one contained the Pfizer product Neurontin 100 mg capsules.

Following discussions with the MHRA’s Defective Medicines Report Centre (DMRC), Reckitt Benckiser (UK) Ltd decided to recall all remaining unexpired stock of Nurofen Plus tablets in any pack size, leading to a Class-1 Drug Alert. The contamination was later traced to in-store tampering by a customer.

What is Ziprasidone?

Introduction

Ziprasidone, sold under the brand name Geodon among others, is an atypical antipsychotic used to treat schizophrenia and bipolar disorder.

It may be used by mouth and by injection into a muscle (IM). The IM form may be used for acute agitation in people with schizophrenia.

Common side effects include dizziness, drowsiness, dry mouth, and twitches. Although it can also cause weight gain, the risk is much lower than for other atypical antipsychotics. How it works is not entirely clear but is believed to involve effects on serotonin and dopamine in the brain.

Ziprasidone was approved for medical use in the United States in 2001. The pills are made up of the hydrochloride salt, ziprasidone hydrochloride. The intramuscular form is the mesylate, ziprasidone mesylate trihydrate, and is provided as a lyophilised powder. In 2017, it was the 261st most commonly prescribed medication in the United States, with more than one million prescriptions.

Brief History

Ziprasidone is chemically similar to risperidone, of which it is a structural analogue. It was first synthesized in 1987 at the Pfizer central research campus in Groton, Connecticut.

Phase I trials started in 1995. In 1998 ziprasidone was approved in Sweden. After the FDA raised concerns about long QT syndrome, more clinical trials were conducted and submitted to the FDA, which approved the drug on 05 February 2001.

Medical Uses

Ziprasidone is approved by the US Food and Drug Administration (FDA) for the treatment of schizophrenia as well as acute mania and mixed states associated with bipolar disorder. Its intramuscular injection form is approved for acute agitation in schizophrenic patients for whom treatment with just ziprasidone is appropriate.

In a 2013 study in a comparison of 15 antipsychotic drugs in effectiveness in treating schizophrenic symptoms, ziprasidone demonstrated mild-standard effectiveness. 15% more effective than lurasidone and iloperidone, approximately as effective as chlorpromazine and asenapine, and 9-13% less effective than haloperidol, quetiapine, and aripiprazole. Ziprasidone is effective in the treatment of schizophrenia, though evidence from the CATIE trials suggests it is less effective than olanzapine, and equally as effective compared to quetiapine. There are higher discontinuation rates for lower doses of ziprasidone, which are also less effective than higher doses.

Adverse Effects

Ziprasidone (and all other second generation antipsychotics (SGAs)) received a black box warning due to increased mortality in elderly patients with dementia-related psychosis.

Sleepiness and headache are very common adverse effects (>10%).

Common adverse effects (1-10%), include producing too much saliva or having dry mouth, runny nose, respiratory disorders or coughing, nausea and vomiting, stomach aches, constipation or diarrhoea, loss of appetite, weight gain (but the smallest risk for weight gain compared to other antipsychotics), rashes, fast heart beats, blood pressure falling when standing up quickly, muscle pain, weakness, twitches, dizziness, and anxiety. Extrapyramidal symptoms are also common and include tremor, dystonia (sustained or repetitive muscle contractions), akathisia (the feeling of a need to be in motion), parkinsonism, and muscle rigidity; in a 2013 meta-analysis of 15 antipsychotic drugs, ziprasidone ranked 8th for such side effects.

Ziprasidone is known to cause activation into mania in some bipolar patients.

This medication can cause birth defects, according to animal studies, although this side effect has not been confirmed in humans.

Recently, the FDA required the manufacturers of some atypical antipsychotics to include a warning about the risk of hyperglycaemia and Type II diabetes with atypical antipsychotics. Some evidence suggests that ziprasidone does not cause insulin resistance to the degree of other atypical antipsychotics, such as olanzapine. Weight gain is also less of a concern with ziprasidone compared to other atypical antipsychotics. In fact, in a trial of long term therapy with ziprasidone, overweight patients (BMI > 27) actually had a mean weight loss overall. According to the manufacturer insert, ziprasidone caused an average weight gain of 2.2 kg (4.8 lbs), which is significantly lower than other atypical antipsychotics, making this medication better for patients that are concerned about their weight. In December 2014, the FDA warned that ziprasidone could cause a potentially fatal skin reaction, Drug Reaction with Eosinophilia and Systemic Symptoms, although this was believed to occur only rarely.

Discontinuation

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

There is tentative evidence that discontinuation of antipsychotics can result in psychosis. It may also result in reoccurrence of the condition that is being treated. Rarely tardive dyskinesia can occur when the medication is stopped.

Pharmacology

Pharmacodynamics

Correspondence to Clinical Effects

Ziprasidone mostly affects the receptors of dopamine (D2), serotonin (5-HT2A, partially 5-HT1A, 5-HT2C, and 5-HT1D) and epinephrine/norepinephrine (α1) to a high degree, while of histamine (H1) – moderately. It also somewhat inhibits reuptake of serotonin and norepinephrine, though not dopamine.

Ziprasidone’s efficacy in treating the positive symptoms of schizophrenia is believed to be mediated primarily via antagonism of the dopamine receptors, specifically D2. Blockade of the 5-HT2A receptor may also play a role in its effectiveness against positive symptoms, though the significance of this property in antipsychotic drugs is still debated among researchers. Blockade of 5-HT2A and 5-HT2C and activation of 5-HT1A as well as inhibition of the reuptake of serotonin and norepinephrine may all contribute to its ability to alleviate negative symptoms. The relatively weak antagonistic actions of ziprasidone on the α1-adrenergic receptor likely in part explains some of its side effects, such as orthostatic hypotension. Unlike many other antipsychotics, ziprasidone has no significant affinity for the mACh receptors, and as such lacks any anticholinergic side effects. Like most other antipsychotics, ziprasidone is sedating due primarily to serotonin and dopamine blockade.

Pharmacokinetics

The systemic bioavailability of ziprasidone is 100% when administered intramuscularly and 60% when administered orally without food.

After a single dose intramuscular administration, the peak serum concentration typically occurs at about 60 minutes after the dose is administered, or earlier. Steady state plasma concentrations are achieved within one to three days. Exposure increases in a dose-related manner and following three days of intramuscular dosing, little accumulation is observed.

The bioavailability of the drug is reduced by approximately 50% if a meal is not eaten before Ziprasidone ingestion.

Ziprasidone is hepatically metabolized by aldehyde oxidase; minor metabolism occurs via cytochrome P450 3A4 (CYP3A4). Medications that induce (e.g. carbamazepine) or inhibit (e.g. ketoconazole) CYP3A4 have been shown to decrease and increase, respectively, blood levels of ziprasidone.

Its biological half-life time is 10 hours at doses of 80-120 milligrams.

Society and Culture

Lawsuit

In September 2009, the US Justice Department announced that Pfizer had been ordered to pay a historic fine of $2.3 billion as a penalty for fraudulent marketing of several drugs, including Geodon. Pfizer had illegally promoted Geodon and submitted false claims to government health care programs for uses that were not medically accepted indications. The civil settlement also resolves allegations that Pfizer paid kickbacks to health care providers to induce them to prescribe Geodon, as well as other drugs. This was the largest civil fraud settlement in history against a pharmaceutical company.

What is an Antipsychotic?

Introduction

Antipsychotics, also known as neuroleptics, are a class of psychotropic medication primarily used to manage psychosis (including delusions, hallucinations, paranoia or disordered thought), principally in schizophrenia but also in a range of other psychotic disorders.

They are also the mainstay together with mood stabilisers in the treatment of bipolar disorder.

Recent research has shown that use of any antipsychotic results in smaller brain tissue volumes and that this brain shrinkage is dose dependent and time dependent. A review of the research has also reinforced this effect.

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.

First-generation antipsychotics, known as typical antipsychotics, were first introduced in the 1950s, and others were developed until the early 1970s. Second-generation drugs, known as atypical antipsychotics, were introduced firstly with clozapine in the early 1970s followed by others. Both generations of medication block receptors in the brain for dopamine, but atypicals tend to act on serotonin receptors as well. Neuroleptic, originating from Greek: νεῦρον (neuron) and λαμβάνω (take hold of) – thus meaning “which takes the nerve” – refers to both common neurological effects and side effects.

Brief History

The original antipsychotic drugs were happened upon largely by chance and then tested for their effectiveness. The first, chlorpromazine, was developed as a surgical anaesthetic. It was first used on psychiatric patients because of its powerful calming effect; at the time it was regarded as a non-permanent “pharmacological lobotomy”. Lobotomy at the time was used to treat many behavioural disorders, including psychosis, although its effect was to markedly reduce behaviour 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 discovered by an approach that incorporates this sort of information.

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, non-manic patients, and Jean Delay and Pierre Deniker described it as controlling manic or psychotic agitation. The former claimed to have discovered a treatment for agitation in anyone, and the latter team claimed to have discovered a treatment for psychotic illness.

Until the 1970s there was considerable debate within psychiatry on the most appropriate term to use to describe the new drugs. In the late 1950s the most widely used term was “neuroleptic”, followed by “major tranquilizer” and then “ataraxic”. The first recorded use of the term tranquilizer dates from the early nineteenth century. In 1953 Frederik F. Yonkman, a chemist at the Swiss-based Cibapharmaceutical company, first used the term tranquiliser to differentiate reserpine from the older sedatives. The word neuroleptic was coined in 1955 by Delay and Deniker after their discovery (1952) of the antipsychotic effects of chlorpromazine. It is derived from the Greek: “νεῦρον” (neuron, originally meaning “sinew” but today referring to the nerves) and “λαμβάνω” (lambanō, meaning “take hold of”). Thus, the word means taking hold of one’s nerves. It was often taken to refer also to common side effects such as reduced activity in general, as well as lethargy and impaired motor control. Although these effects are unpleasant and in some cases harmful, they were at one time, along with akathisia, considered a reliable sign that the drug was working. The term “ataraxy” was coined by the neurologist Howard Fabing and the classicist Alister Cameron to describe the observed effect of psychic indifference and detachment in patients treated with chlorpromazine. This term derived from the Greek adjective “ἀτάρακτος” (ataraktos), which means “not disturbed, not excited, without confusion, steady, calm”. In the use of the terms “tranquiliser” and “ataractic”, medical practitioners distinguished between the “major tranquilizers” or “major ataractics”, which referred to drugs used to treat psychoses, and the “minor tranquilizers” or “minor ataractics”, which referred to drugs used to treat neuroses. While popular during the 1950s, these terms are infrequently used today. They are being abandoned in favour of “antipsychotic”, which refers to the drug’s desired effects. Today, “minor tranquiliser” can refer to anxiolytic and/or hypnotic drugs such as the benzodiazepines and nonbenzodiazepines, which have some antipsychotic properties and are recommended for concurrent use with antipsychotics, and are useful for insomnia or drug-induced psychosis. 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.

Medical Uses

Antipsychotics are most frequently used for the following conditions:

  • Schizophrenia.
  • Schizoaffective disorder most commonly in conjunction with either an antidepressant (in the case of the depressive subtype) or a mood stabiliser (in the case of the bipolar subtype).
  • Bipolar disorder (acute mania and mixed episodes) may be treated with either typical or atypical antipsychotics, although atypical antipsychotics are usually preferred because they tend to have more favourable adverse effect profiles and, according to a recent meta-analysis, they tend to have a lower liability for causing conversion from mania to depression.
  • Psychotic depression. In this indication it is a common practice for the psychiatrist to prescribe a combination of an atypical antipsychotic and an antidepressant as this practice is best supported by the evidence.
  • Treatment resistant depression as an adjunct to standard antidepressant therapy.

Antipsychotics are generally not recommended for treating behavioural problems associated with dementia, given that the risk of use tends to be greater than the potential benefit. The same can be said for insomnia, in which they are not recommended as first-line therapy. There are evidence-based indications for using antipsychotics in children (e.g. tic disorder, bipolar disorder, psychosis), but the use of antipsychotics outside of those contexts (e.g. to treat behavioural problems) warrants significant caution.

Schizophrenia

Antipsychotic drug treatment is a key component of schizophrenia treatment recommendations by the National Institute of Health and Care Excellence (NICE), the American Psychiatric Association, and the British Society for Psychopharmacology. The main aim of treatment with antipsychotics is to reduce the positive symptoms of psychosis that include delusions and hallucinations. There is mixed evidence to support a significant impact of antipsychotic use on negative symptoms (such as apathy, lack of emotional affect, and lack of interest in social interactions) or on the cognitive symptoms (memory impairments, reduced ability to plan and execute tasks). In general, the efficacy of antipsychotic treatment in reducing both positive and negative symptoms appears to increase with increasing severity of baseline symptoms. All antipsychotic medications work relatively the same way, by antagonising D2 dopamine receptors. However, there are some differences when it comes to typical and atypical antipsychotics. For example, atypical antipsychotic medications have been seen to lower the neurocognitive impairment associated with schizophrenia more so than conventional antipsychotics, although the reasoning and mechanics of this are still unclear to researchers.

Applications of antipsychotic drugs in the treatment of schizophrenia include prophylaxis in those showing symptoms that suggest that they are at high risk of developing psychosis, treatment of first episode psychosis, maintenance therapy (a form of prophylaxis, maintenance therapy aims to maintain therapeutic benefit and prevent symptom relapse), and treatment of recurrent episodes of acute psychosis.

Prevention of Psychosis and Symptom Improvement

Test batteries such as the PACE (Personal Assessment and Crisis Evaluation Clinic) and COPS (Criteria of Prodromal Syndromes), which measure low-level psychotic symptoms and cognitive disturbances, are used to evaluate people with early, low-level symptoms of psychosis. Test results are combined with family history information to identify patients in the “high-risk” group; they are considered to have a 20-40% risk of progression to frank psychosis within two years. These patients are often treated with low doses of antipsychotic drugs with the goal of reducing their symptoms and preventing progression to frank psychosis. While generally useful for reducing symptoms, clinical trials to date show little evidence that early use of antipsychotics improves long-term outcomes in those with prodromal symptoms, either alone or in combination with cognitive behavioural therapy (CBT).

First Episode Psychosis

First episode psychosis (FEP), is the first time that psychotic symptoms are presented. NICE recommends that all persons presenting with first episode psychosis be treated with both an antipsychotic drug, and CBT. NICE further recommends that those expressing a preference for CBT alone are informed that combination treatment is more effective. A diagnosis of schizophrenia is not made at this time as it takes longer to determine by both DSM-5 and ICD-11, and only around 60% of those presenting with a first episode psychosis will later be diagnosed with schizophrenia.

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

Pharmacological options for the specific treatment of FEP have been discussed in recent reviews. The goals of treatment for FEP include reducing symptoms and potentially improving long-term treatment outcomes. Randomised clinical trials have provided evidence for the efficacy of antipsychotic drugs in achieving the former goal, with first-generation and second generation antipsychotics showing about equal efficacy. Evidence that early treatment has a favourable effect on long term outcomes is equivocal.

Recurrent Psychotic Episodes

Placebo controlled trials of both first and second generation antipsychotic drugs consistently demonstrate the superiority of active drug to placebo in suppressing psychotic symptoms. A large meta-analysis of 38 trials of antipsychotic drugs in schizophrenia acute psychotic episodes showed an effect size of about 0.5. There is little or no difference in efficacy among approved antipsychotic drugs, including both first- and second-generation agents. The efficacy of such drugs is suboptimal. Few patients achieve complete resolution of symptoms. Response rates, calculated using various cutoff values for symptom reduction, are low and their interpretation is complicated by high placebo response rates and selective publication of clinical trial results.

Maintenance Therapy

The majority of patients treated with an antipsychotic drug will experience a response within four weeks. The goals of continuing treatment are to maintain suppression of symptoms, prevent relapse, improve quality of life, and support engagement in psychosocial therapy.

Maintenance therapy with antipsychotic drugs is clearly superior to placebo in preventing relapse but is associated with weight gain, movement disorders, and high dropout rates. A 3-year trial following persons receiving maintenance therapy after an acute psychotic episode found that 33% obtained long-lasting symptom reduction, 13% achieved remission, and only 27% experienced satisfactory quality of life. The effect of relapse prevention on long term outcomes is uncertain, as historical studies show little difference in long term outcomes before and after the introduction of antipsychotic drugs.

While maintenance therapy clearly reduces the rate of relapses requiring hospitalization, a large observational study in Finland found that, in people that eventually discontinued antipsychotics, the risk of being hospitalized again for a mental health problem or dying increased the longer they were dispensed (and presumably took) antipsychotics prior to stopping therapy. If people did not stop taking antipsychotics, they remained at low risk for relapse and hospitalisation compared to those that stopped taking antipsychotics. The authors speculated that the difference may be because the people that discontinued treatment after a longer time had more severe mental illness than those that discontinued antipsychotic therapy sooner.

A significant challenge in the use of antipsychotic drugs for the prevention of relapse is the poor rate of adherence. In spite of the relatively high rates of adverse effects associated with these drugs, some evidence, including higher dropout rates in placebo arms compared to treatment arms in randomised clinical trials, suggest that most patients who discontinue treatment do so because of suboptimal efficacy. If someone experiences psychotic symptoms due to nonadherence, they may be compelled to treatment through a process called involuntary commitment, in which they can be forced to accept treatment (including antipsychotics). A person can also be committed to treatment outside of a hospital, called outpatient commitment.

Antipsychotics in long-acting injectable (LAI), or “depot”, form have been suggested as a method of decreasing medication nonadherence (sometimes also called non-compliance). NICE advises LAIs be offered to patients when preventing covert, intentional nonadherence is a clinical priority. LAIs are used to ensure adherence in outpatient commitment. A meta-analysis found that LAIs resulted in lower rates of rehospitalisation with a hazard ratio of 0.83, however these results were not statistically significant (the 95% confidence interval was 0.62 to 1.11).

Bipolar Disorder

Antipsychotics are routinely used, often in conjunction with mood stabilisers such as lithium/valproate, as a first-line treatment for manic and mixed episodes associated with bipolar disorder. The reason for this combination is the therapeutic delay of the aforementioned mood stabilisers (for valproate therapeutic effects are usually seen around five days after treatment is commenced whereas lithium usually takes at least a week before the full therapeutic effects are seen) and the comparatively rapid antimanic effects of antipsychotic drugs. The antipsychotics have a documented efficacy when used alone in acute mania/mixed episodes.

Three atypical antipsychotics (lurasidone, olanzapine and quetiapine) have also been found to possess efficacy in the treatment of bipolar depression as a monotherapy, whereas only olanzapine and quetiapine have been proven to be effective broad-spectrum (i.e. against all three types of relapse – manic, mixed and depressive) prophylactic (or maintenance) treatments in patients with bipolar disorder. A recent Cochrane review also found that olanzapine had a less favourable risk/benefit ratio than lithium as a maintenance treatment for bipolar disorder.

The American Psychiatric Association and the UK National Institute for Health and Care Excellence recommend antipsychotics for managing acute psychotic episodes in schizophrenia or bipolar disorder, and as a longer-term maintenance treatment for reducing the likelihood of further episodes. They state that response to any given antipsychotic can be variable so that trials may be necessary, and that lower doses are to be preferred where possible. A number of studies have looked at levels of “compliance” or “adherence” with antipsychotic regimes and found that discontinuation (stopping taking them) by patients is associated with higher rates of relapse, including hospitalisation.

Dementia

Psychosis and agitation develop in as many as 80 percent of people living in nursing homes. Despite a lack of Federal Drug Administration (FDA) approval and black-box warnings, atypical antipsychotics are often prescribed to people with dementia. An assessment for an underlying cause of behaviour is needed before prescribing antipsychotic medication for symptoms of dementia. Antipsychotics in old age dementia showed a modest benefit compared to placebo in managing aggression or psychosis, but this is combined with a fairly large increase in serious adverse events. Thus, antipsychotics should not be used routinely to treat dementia with aggression or psychosis, but may be an option in a few cases where there is severe distress or risk of physical harm to others. Psychosocial interventions may reduce the need for antipsychotics. In 2005, the FDA issued an advisory warning of an increased risk of death when atypical antipsychotics are used in dementia. In the subsequent 5 years, the use of atypical antipsychotics to treat dementia decreased by nearly 50%.

Major Depressive Disorder

A number of atypical antipsychotics have some benefits when used in addition to other treatments in major depressive disorder. Aripiprazole, quetiapine extended-release, and olanzapine (when used in conjunction with fluoxetine) have received FDA labelling for this indication. There is, however, a greater risk of side effects with their use compared to using traditional antidepressants. The greater risk of serious side effects with antipsychotics is why, e.g. quetiapine was denied approval as monotherapy for major depressive disorder or generalised anxiety disorder, and instead was only approved as an adjunctive treatment in combination with traditional antidepressants.

Other

Besides the above uses antipsychotics may be used for obsessive compulsive disorder (OCD), post-traumatic stress disorder (PTSD), personality disorders, Tourette syndrome, autism and agitation in those with dementia. Evidence however does not support the use of atypical antipsychotics in eating disorders or personality disorder. The atypical antipsychotic risperidone may be useful for OCD. The use of low doses of antipsychotics for insomnia, while common, is not recommended as there is little evidence of benefit and concerns regarding adverse effects. Low dose antipsychotics may also be used in treatment of impulse-behavioural and cognitive-perceptual symptoms of borderline personality disorder.

In children they may be used in those with disruptive behaviour disorders, mood disorders and pervasive developmental disorders or intellectual disability. Antipsychotics are only weakly recommended for Tourette syndrome, because although they are effective, side effects are common. The situation is similar for those on the autism spectrum. Much of the evidence for the off-label use of antipsychotics (for example, for dementia, OCD, PTSD, personality disorders, Tourette’s) was of insufficient scientific quality to support such use, especially as there was strong evidence of increased risks of stroke, tremors, significant weight gain, sedation, and gastrointestinal problems. A UK review of unlicensed usage in children and adolescents reported a similar mixture of findings and concerns. A survey of children with pervasive developmental disorder found that 16.5% were taking an antipsychotic drug, most commonly for irritability, aggression, and agitation. Both risperidone and aripiprazole have been approved by the FDA for the treatment of irritability in autistic children and adolescents.

Aggressive challenging behaviour in adults with intellectual disability is often treated with antipsychotic drugs despite lack of an evidence base. A recent randomised controlled trial, however, found no benefit over placebo and recommended that the use of antipsychotics in this way should no longer be regarded as an acceptable routine treatment.

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

Typicals vs Atypicals

It is unclear whether the atypical (second-generation) antipsychotics offer advantages over older, first generation antipsychotics. Amisulpride, olanzapine, risperidone and clozapine may be more effective but are associated with greater side effects. Typical antipsychotics have equal drop-out and symptom relapse rates to atypicals when used at low to moderate dosages.

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

Due to bias in the research the accuracy of comparisons of atypical antipsychotics is a concern.

In 2005, a US government body, the National Institute of Mental Health published the results of a major independent study (the CATIE project). No other atypical studied (risperidone, quetiapine, and ziprasidone) did better than the typical perphenazine on the measures used, nor did they produce fewer adverse effects than the typical antipsychotic perphenazine, although more patients discontinued perphenazine owing to extrapyramidal effects compared to the atypical agents (8% vs. 2% to 4%).

Atypical antipsychotics do not appear to lead to improved rates of medication adherence compared to typical antipsychotics.

Many researchers question the first-line prescribing of atypicals over typicals, and some even question the distinction between the two classes. In contrast, other researchers point to the significantly higher risk of tardive dyskinesia and other extrapyramidal symptoms with the typicals and for this reason alone recommend first-line treatment with the atypicals, notwithstanding a greater propensity for metabolic adverse effects in the latter. NICE recently revised its recommendation favouring 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 atypical

Adverse Effects

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

Very rarely antipsychotics may cause tardive psychosis.

By Rate

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

  • Sedation (particularly common with asenapine, clozapine, olanzapine, quetiapine, chlorpromazine and zotepine).
  • Headaches.
  • Dizziness.
  • Diarrhoea.
  • Anxiety.
  • Extrapyramidal side effects (particularly common with first-generation antipsychotics), which include:
    • Akathisia, an often distressing sense of inner restlessness.
    • Dystonia, an abnormal muscle contraction.
    • Pseudoparkinsonism, symptoms that are similar to what people with Parkinson’s disease experience, including tremulousness and drooling.
  • Hyperprolactinaemia (rare for those treated with clozapine, quetiapine and aripiprazole), which can cause:
    • Galactorrhoea, the unusual secretion of breast milk.
    • Gynaecomastia, abnormal growth of breast tissue.
    • Sexual dysfunction (in both sexes).
    • Osteoporosis.
  • Orthostatic hypotension.
  • Weight gain (particularly prominent with clozapine, olanzapine, quetiapine and zotepine).
  • Anticholinergic side-effects (common for olanzapine, clozapine; less likely on risperidone) such as:
    • Blurred vision.
    • Constipation.
    • Dry mouth (although hypersalivation may also occur).
    • Reduced perspiration.
  • Tardive dyskinesia appears to be more frequent with high-potency first-generation antipsychotics, such as haloperidol, and tends to appear after chronic and not acute treatment. It is characterised 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).

Rare/Uncommon (<1% incidence for most antipsychotic drugs) adverse effects of antipsychotics include:

  • Blood dyscrasias (e.g., agranulocytosis, leukopenia, and neutropoenia), which is more common in patients on clozapine.
  • Metabolic syndrome and other metabolic problems such as type II diabetes mellitus – particularly common with clozapine, olanzapine and zotepine. In American studies African Americans appeared to be at a heightened risk for developing type II diabetes mellitus. Evidence suggests that females are more sensitive to the metabolic side effects of first-generation antipsychotic drugs than males. Metabolic adverse effects appear to be mediated by the following mechanisms:
    • Causing weight gain by antagonising the histamine H1 and serotonin 5-HT2Creceptors] and perhaps by interacting with other neurochemical pathways in the central nervous system.
  • Neuroleptic malignant syndrome, a potentially fatal condition characterised 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.
  • QT interval prolongation – more prominent in those treated with amisulpride, pimozide, sertindole, thioridazine and ziprasidone.
  • Torsades de pointes.
  • Seizures, particularly in people treated with chlorpromazine and clozapine.
  • Thromboembolism.
  • Myocardial infarction.
  • Stroke.

Long-Term Effects

Some studies have found decreased life expectancy associated with the use of antipsychotics, and argued that more studies are needed. Antipsychotics may also increase the risk of early death in individuals with dementia. Antipsychotics typically worsen symptoms in people who suffer from depersonalisation disorder. Antipsychotic polypharmacy (prescribing two or more antipsychotics at the same time for an individual) is a common practice but not evidence-based or recommended, and there are initiatives to curtail it. Similarly, the use of excessively high doses (often the result of polypharmacy) continues despite clinical guidelines and evidence indicating that it is usually no more effective but is usually more harmful.

Loss of grey matter and other brain structural changes over time are observed amongst people diagnosed with schizophrenia. Meta-analyses of the effects of antipsychotic treatment on grey matter volume and the brain’s structure have reached conflicting conclusions. A 2012 meta-analysis concluded that grey matter loss is greater in patients treated with first generation antipsychotics relative to those treated with atypicals, and hypothesized a protective effect of atypicals as one possible explanation. A second meta-analysis suggested that treatment with antipsychotics was associated with increased grey matter loss. Animal studies found that monkeys exposed to both first- and second-generation antipsychotics experience significant reduction in brain volume, resulting in an 8-11% reduction in brain volume over a 17-27 month period.

Subtle, long-lasting forms of akathisia are often overlooked or confused with post-psychotic depression, in particular when they lack the extrapyramidal aspect that psychiatrists have been taught to expect when looking for signs of akathisia.

Adverse effect on cognitive function and increased risk of death in people with dementia along with worsening of symptoms has been describe in the literature.

Discontinuation

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

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

Unexpected psychotic episodes have been observed in patients withdrawing from clozapine. This is referred to as supersensitivity psychosis, not to be equated with tardive dyskinesia.

Tardive dyskinesia may abate during withdrawal from the antipsychotic agent, or it may persist.

Withdrawal effects may also occur when switching a person from one antipsychotic to another, (it is presumed due to variations of potency and receptor activity). Such withdrawal effects can include cholinergic rebound, an activation syndrome, and motor syndromes including dyskinesias. These adverse effects are more likely during rapid changes between antipsychotic agents, so making a gradual change between antipsychotics minimises these withdrawal effects. The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotic treatment to avoid acute withdrawal syndrome or rapid relapse. The process of cross-titration involves gradually increasing the dose of the new medication while gradually decreasing the dose of the old medication.

City and Hackney Clinical Commissioning Group found more than 1,000 patients in their area in July 2019 who had not had regular medication reviews or health checks because they were not registered as having serious mental illness. On average they had been taking these drugs for six years. If this is typical of practice in England more than 100,000 patients are probably in the same position.

List of Agents

Clinically used antipsychotic medications are listed below by drug group. Trade names appear in parentheses. A 2013 review has stated that the division of antipsychotics into first and second generation is perhaps not accurate.

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)

  • Butyrophenones:
    • Benperidol‡
    • Bromperidol†
    • Droperidol‡
    • Haloperidol
    • Moperone (discontinued)†
    • Pipamperone (discontinued)†
    • Timiperone †
  • Diphenylbutylpiperidines:
    • Fluspirilene ‡
    • Penfluridol ‡
    • Pimozide
  • Phenothiazines:
    • Acepromazine † – although it is mostly used in veterinary medicine.
    • Chlorpromazine
    • 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:
    • 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)

  • Benzamides:
    • Amisulpride ‡ – Selective dopamine antagonist. Higher doses (greater than 400 mg) act upon post-synaptic dopamine receptors resulting in a reduction in the positive symptoms of schizophrenia, such as psychosis. Lower doses, however, act upon dopamine autoreceptors, resulting in increased dopamine transmission, improving the negative symptoms of schizophrenia. Lower doses of amisulpride have also been shown to have antidepressant and anxiolytic effects in non-schizophrenic patients, leading to its use in dysthymia and social phobias.
    • Nemonapride † – Used in Japan.
    • Remoxipride # – Has a risk of causing aplastic anaemia and, hence, has been withdrawn from the market worldwide. It has also been found to possess relatively low (virtually absent) potential to induce hyperprolactinaemia and extrapyramidal symptoms, likely attributable to its comparatively weak binding to (and, hence, rapid dissociation from) the D2 receptor.
    • Sultopride – An atypical antipsychotic of the benzamide chemical class used in Europe, Japan, and Hong Kong for the treatment of schizophrenia. It was launched by Sanofi-Aventis in 1976. Sultopride acts as a selective D2 and D3 receptor antagonist.
  • Benzisoxazoles/benzisothiazoles:
    • Iloperidone – Approved by the 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.
    • Lurasidone – Approved by the FDA for schizophrenia and bipolar depression, and for use as schizophrenia treatment in Canada.
    • Paliperidone – Primary, active metabolite of risperidone that was approved in 2006.
    • Paliperidone palmitate – Long-acting version of paliperidone for once-monthly injection.
    • Perospirone † – Has a higher incidence of extrapyramidal side effects than other atypical antipsychotics.
    • Risperidone – Divided dosing is recommended until initial titration is completed, at which time the drug can be administered once daily. Used off-label to treat Tourette syndrome and anxiety disorder.
    • Ziprasidone – Approved in 2004 to treat bipolar disorder. Side-effects include a prolonged QT interval in the heart, which can be dangerous for patients with heart disease or those taking other drugs that prolong the QT interval.
  • Butyrophenones:
    • Melperone † – Only used in a few European countries. No English-speaking country has licensed it to date.
    • Lumateperone.
  • Phenylpiperazines/quinolinones:
    • Aripiprazole – Partial agonist at the D2 receptor unlike almost all other clinically-utilized antipsychotics.
    • Aripiprazole lauroxil – Long-acting version of aripiprazole for injection.
    • Brexpiprazole – Partial agonist of the D2 receptor. Successor of aripiprazole.
    • Cariprazine – A D3-preferring D2/D3 partial agonist.
  • Tricyclics:
    • Asenapine – Used for the treatment of schizophrenia and acute mania associated with bipolar disorder.
    • Clozapine – Requires routine laboratory monitoring of complete blood counts every one to four weeks due to the risk of agranulocytosis. It has unparalleled efficacy in the treatment of treatment-resistant schizophrenia.
    • Olanzapine – Used to treat psychotic disorders including schizophrenia, acute manic episodes, and maintenance of bipolar disorder. Used as an adjunct to antidepressant therapy, either alone or in combination with fluoxetine as Symbyax.
    • Quetiapine – Used primarily to treat bipolar disorder and schizophrenia. Also used and licensed in a few countries (including Australia, the United Kingdom and the United States) as an adjunct to antidepressant therapy in patients with major depressive disorder. It is the only antipsychotic that has demonstrated efficacy as a monotherapy for the treatment of major depressive disorder. It indirectly serves as a norepinephrine reuptake inhibitor by means of its active metabolite, norquetiapine.
    • Zotepine – An atypical antipsychotic indicated for acute and chronic schizophrenia. It is still used in Japan and was once used in Germany but it was discontinued.†
  • Others:
    • Blonanserin – Approved by the PMDA in 2008. Used in Japan and South Korea.
    • Pimavanserin – A selective 5-HT2A receptor antagonist approved for the treatment of Parkinson’s disease psychosis in 2016.
    • Sertindole ‡ – Developed by the Danish pharmaceutical company H. Lundbeck. Like the other atypical antipsychotics, it is believed to have antagonist activity at dopamine and serotonin receptors in the brain.

Mechanism of Action

Antipsychotic drugs such as haloperidol and chlorpromazine tend to block dopamine D2 receptors in the dopaminergic pathways of the brain. This means that dopamine released in these pathways has less effect. Excess release of dopamine in the mesolimbic pathway has been linked to psychotic experiences. Decreased dopamine release in the prefrontal cortex, and excess dopamine release in other pathways, are associated with psychotic episodes in schizophrenia and bipolar disorder. In addition to the antagonistic effects of dopamine, antipsychotics (in particular atypical neuroleptics) also antagonise 5-HT2A receptors. Different alleles of the 5-HT2A receptor have been associated with schizophrenia and other psychoses, including depression. Higher concentrations of 5-HT2A receptors in cortical and subcortical areas, in particular in the right caudate nucleus have been historically recorded.

Typical antipsychotics are not particularly selective and also block dopamine receptors in the mesocortical pathway, tuberoinfundibular pathway, and the nigrostriatal pathway. Blocking D2 receptors in these other pathways is thought to produce some unwanted side effects that the typical antipsychotics can produce (see above). They were commonly classified on a spectrum of low potency to high potency, where potency referred to the ability of the drug to bind to dopamine receptors, and not to the effectiveness of the drug. High-potency antipsychotics such as haloperidol, in general, have doses of a few milligrams and cause less sleepiness and calming effects than low-potency antipsychotics such as chlorpromazine and thioridazine, which have dosages of several hundred milligrams. The latter have a greater degree of anticholinergic and antihistaminergic activity, which can counteract dopamine-related side-effects.

Atypical antipsychotic drugs have a similar blocking effect on D2 receptors; however, most also act on serotonin receptors, especially 5-HT2A and 5-HT2C receptors. Both clozapine and quetiapine appear to bind just long enough to elicit antipsychotic effects but not long enough to induce extrapyramidal side effects and prolactin hypersecretion. 5-HT2A antagonism increases dopaminergic activity in the nigrostriatal pathway, leading to a lowered extrapyramidal side effect liability among the atypical antipsychotics.

Society and Culture

Terminology

The term major tranquiliser was used for older antipsychotic drugs. The term neuroleptic is often used as a synonym for antipsychotic, even though – strictly speaking – the two terms are not interchangeable. Antipsychotic drugs are a subgroup of neuroleptic drugs, because the latter have a wider range of effects.

Antipsychotics are a type of psychoactive or psychotropic medication.

Sales

Antipsychotics were once among the biggest selling and most profitable of all drugs, generating $22 billion in global sales in 2008. By 2003 in the US, an estimated 3.21 million patients received antipsychotics, worth an estimated $2.82 billion. Over 2/3 of prescriptions were for the newer, more expensive atypicals, each costing on average $164 per year, compared to $40 for the older types. By 2008, sales in the US reached $14.6 billion, the biggest selling drugs in the US by therapeutic class.

Overprescription

Antipsychotics in the nursing home population are often overprescribed, often for the purposes of making it easier to handle dementia patients. Federal efforts to reduce the use of antipsychotics in US nursing homes has led to a nationwide decrease in their usage in 2012.

Legal

Antipsychotics are sometimes administered as part of compulsory psychiatric treatment via inpatient (hospital) commitment or outpatient commitment.

Formulations

They may be administered orally or, in some cases, through long-acting (depot) injections administered in the dorsgluteal, ventrogluteal or deltoid muscle. Short-acting parenteral formulations also exist, which are generally reserved for emergencies or when oral administration is otherwise impossible. The oral formulations include immediate release, extended release, and orally disintegrating products (which are not sublingual, and can help ensure that medications are swallowed instead of “cheeked”). Sublingual products (e.g. asenapine) also exist, which must be held under the tongue for absorption. The first transdermal formulation of an antipsychotic (transdermal asenapine, marketed as Secuado), was FDA-approved in 2019.

Recreational Use

Certain second-generation antipsychotics are misused or abused for their sedative, tranquilising, and (paradoxically) “hallucinogenic” effects. The most commonly second-generation antipsychotic implicated is quetiapine. In case reports, quetiapine has been abused in doses taken by mouth (which is how the drug is available from the manufacturer), but also crushed and insufflated or mixed with water for injection into a vein. Olanzapine, another sedating second-generation antipsychotic, has also been misused for similar reasons. There is no standard treatment for antipsychotic abuse, though switching to a second-generation antipsychotic with less abuse potential (e.g. aripiprazole) has been used.

Controversy

Joanna Moncrieff has argued that antipsychotic drug treatment is often undertaken as a means of control rather than to treat specific symptoms experienced by the patient.

Use of this class of drugs has a history of criticism in residential care. As the drugs used can make patients calmer and more compliant, critics claim that the drugs can be overused. Outside doctors can feel under pressure from care home staff. In an official review commissioned by UK government ministers it was reported that the needless use of antipsychotic medication in dementia care was widespread and was linked to 1800 deaths per year. In the US, the government has initiated legal action against the pharmaceutical company Johnson & Johnson for allegedly paying kickbacks to Omnicare to promote its antipsychotic risperidone (Risperdal) in nursing homes.

There has also been controversy about the role of pharmaceutical companies in marketing and promoting antipsychotics, including allegations of downplaying or covering up adverse effects, expanding the number of conditions or illegally promoting off-label usage; influencing drug trials (or their publication) to try to show that the expensive and profitable newer atypicals were superior to the older cheaper typicals that were out of patent. Following charges of illegal marketing, settlements by two large pharmaceutical companies in the US set records for the largest criminal fines ever imposed on corporations. One case involved Eli Lilly and Company’s antipsychotic Zyprexa, and the other involved Bextra. In the Bextra case, the government also charged Pfizer with illegally marketing another antipsychotic, Geodon. In addition, Astrazeneca faces numerous personal-injury lawsuits from former users of Seroquel (quetiapine), amidst federal investigations of its marketing practices. By expanding the conditions for which they were indicated, Astrazeneca’s Seroquel and Eli Lilly’s Zyprexa had become the biggest selling antipsychotics in 2008 with global sales of $5.5 billion and $5.4 billion respectively.

Harvard medical professor Joseph Biederman conducted research on bipolar disorder in children that led to an increase in such diagnoses. A 2008 Senate investigation found that Biederman also received $1.6 million in speaking and consulting fees between 2000 and 2007 – some of them undisclosed to Harvard – from companies including makers of antipsychotic drugs prescribed for children with bipolar disorder. Johnson & Johnson gave more than $700,000 to a research centre that was headed by Biederman from 2002 to 2005, where research was conducted, in part, on Risperdal, the company’s antipsychotic drug. Biederman has responded saying that the money did not influence him and that he did not promote a specific diagnosis or treatment.

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

Special Populations

It is recommended that persons with dementia who exhibit behavioural and psychological symptoms should not be given antipsychotics before trying other treatments. When taking antipsychotics this population has increased risk of cerebrovascular effects, parkinsonism or extrapyramidal symptoms, sedation, confusion and other cognitive adverse effects, weight gain, and increased mortality. Physicians and caretakers of persons with dementia should try to address symptoms including agitation, aggression, apathy, anxiety, depression, irritability, and psychosis with alternative treatments whenever antipsychotic use can be replaced or reduced. Elderly persons often have their dementia treated first with antipsychotics and this is not the best management strategy.