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 Imidazenil?

Introduction

Imidazenil is an experimental anxiolytic drug which is derived from the benzodiazepine family, and is most closely related to other imidazobenzodiazepines such as midazolam, flumazenil, and bretazenil.

Outline

Imidazenil is a highly potent benzodiazepine receptor partial agonist with an unusual profile of effects, producing some of the effects associated with normal benzodiazepines such as anticonvulsant and anxiolytic effects, yet without any notable sedative or amnestic effects. In fact, imidazenil blocks the sedative effects of diazepam, yet without lowering the convulsion threshold, and so potentially could be a more flexible antidote than the antagonist flumazenil which is commonly used to treat benzodiazepine overdose at present.

As of August 2021, Imidazenil has not yet been developed commercially for use in humans, however it has been suggested as a safe and effective treatment for anxiety, a potent yet non-sedating anticonvulsant which might be particularly useful in the treatment of poisoning with organophosphate nerve agents, and as a novel treatment for schizophrenia.

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 Haloperidol?

Introduction

Haloperidol, sold under the brand name Haldol among others, is a typical antipsychotic medication.

Haloperidol is used in the treatment of schizophrenia, tics in Tourette syndrome, mania in bipolar disorder, delirium, agitation, acute psychosis, and hallucinations in alcohol withdrawal. It may be used by mouth or injection into a muscle or a vein. Haloperidol typically works within 30 to 60 minutes. A long-acting formulation may be used as an injection every four weeks in people with schizophrenia or related illnesses, who either forget or refuse to take the medication by mouth.

Haloperidol may result in a movement disorder known as tardive dyskinesia which may be permanent. Neuroleptic malignant syndrome and QT interval prolongation may occur. In older people with psychosis due to dementia it results in an increased risk of death. When taken during pregnancy it may result in problems in the infant. It should not be used in people with Parkinson’s disease.

Haloperidol was discovered in 1958 by Paul Janssen. It was made from pethidine (meperidine). It is on the World Health Organisation’s (WHO’s) List of Essential Medicines. It is the most commonly used typical antipsychotic. In 2017, it was the 296th most commonly prescribed medication in the United States, with more than one million prescriptions.

Brief History

Haloperidol was discovered by Paul Janssen. It was developed in 1958 at the Belgian company Janssen Pharmaceutica and submitted to the first of clinical trials in Belgium later that year.

Haloperidol was approved by the US Food and Drug Administration (FDA) on 12 April 1967; it was later marketed in the US and other countries under the brand name Haldol by McNeil Laboratories.

Medical Uses

Haloperidol is used in the control of the symptoms of:

  • Acute psychosis, such as drug-induced psychosis caused by LSD, psilocybin, amphetamines, ketamine, and phencyclidine, and psychosis associated with high fever or metabolic disease.
    • Some evidence, however, has found haloperidol to worsen psychosis due to psilocybin.
  • Adjunctive treatment of alcohol and opioid withdrawal.
  • Agitation and confusion associated with cerebral sclerosis.
  • Alcohol-induced psychosis.
  • Hallucinations in alcohol withdrawal.
  • Hyperactive delirium (to control the agitation component of delirium).
  • Hyperactivity, aggression.
  • Otherwise uncontrollable, severe behavioral disorders in children and adolescents.
  • Schizophrenia.
  • Therapeutic trial in personality disorders, such as borderline personality disorder.
  • Treatment of intractable hiccups.
  • Treatment of neurological disorders, such as tic disorders such as Tourette syndrome, and chorea.
  • Treatment of severe nausea and emesis in postoperative and palliative care, especially for palliating adverse effects of radiation therapy and chemotherapy in oncology.

Haloperidol was considered indispensable for treating psychiatric emergency situations, although the newer atypical drugs have gained a greater role in a number of situations as outlined in a series of consensus reviews published between 2001 and 2005.

In a 2013 comparison of 15 antipsychotics in schizophrenia, haloperidol demonstrated standard effectiveness. It was 13-16% more effective than ziprasidone, chlorpromazine, and asenapine, approximately as effective as quetiapine and aripiprazole, and 10% less effective than paliperidone.

Pregnancy and Lactation

Data from animal experiments indicate haloperidol is not teratogenic, but is embryotoxic in high doses. In humans, no controlled studies exist. Reports in pregnant women revealed possible damage to the foetus, although most of the women were exposed to multiple drugs during pregnancy. In addition, reports indicate neonates exposed to antipsychotic drugs are at risk for extrapyramidal and/or withdrawal symptoms following delivery, such as agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder. Following accepted general principles, haloperidol should be given during pregnancy only if the benefit to the mother clearly outweighs the potential foetal risk.

Haloperidol is excreted in breast milk. A few studies have examined the impact of haloperidol exposure on breastfed infants and in most cases, there were no adverse effects on infant growth and development.

Other Considerations

During long-term treatment of chronic psychiatric disorders, the daily dose should be reduced to the lowest level needed for maintenance of remission. Sometimes, it may be indicated to terminate haloperidol treatment gradually. In addition, during long-term use, routine monitoring including measurement of BMI, blood pressure, fasting blood sugar, and lipids, is recommended due to the risk of side effects.

Other forms of therapy (psychotherapy, occupational therapy/ergotherapy, or social rehabilitation) should be instituted properly. PET imaging studies have suggested low doses are preferable. Clinical response was associated with at least 65% occupancy of D2 receptors, while greater than 72% was likely to cause hyperprolactinaemia and over 78% associated with extrapyramidal side effects. Doses of haloperidol greater than 5 mg increased the risk of side effects without improving efficacy. Patients responded with doses under even 2 mg in first-episode psychosis. For maintenance treatment of schizophrenia, an international consensus conference recommended a reduction dosage by about 20% every 6 months until a minimal maintenance dose is established.

Depot forms are also available; these are injected deeply intramuscularly at regular intervals. The depot forms are not suitable for initial treatment, but are suitable for patients who have demonstrated inconsistency with oral dosages.

The decanoate ester of haloperidol (haloperidol decanoate, trade names Haldol decanoate, Halomonth, Neoperidole) has a much longer duration of action, so is often used in people known to be noncompliant with oral medication. A dose is given by intramuscular injection once every two to four weeks. The IUPAC name of haloperidol decanoate is [4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]piperidin-4-yl] decanoate.

Topical formulations of haloperidol should not be used as treatment for nausea because research does not indicate this therapy is more effective than alternatives.

Adverse Effects

As haloperidol is a high-potency typical antipsychotic, it tends to produce significant extrapyramidal side effects. According to a 2013 meta-analysis of the comparative efficacy and tolerability of 15 antipsychotic drugs it was the most prone of the 15 for causing extrapyramidal side effects.

With more than 6 months of use 14 percent of users gain weight. Haloperidol may be neurotoxic.

  • Common (>1% incidence):
    • Extrapyramidal side effects including:
      • Akathisia (motor restlessness).
      • Dystonia (continuous spasms and muscle contractions).
      • Muscle rigidity.
      • Parkinsonism (characteristic symptoms such as rigidity).
    • Hypotension:
    • Anticholinergic side effects such as (These adverse effects are less common than with lower-potency typical antipsychotics, such as chlorpromazine and thioridazine):
      • Blurred vision.
      • Constipation.
      • Dry mouth.
    • Somnolence (which is not a particularly prominent side effect, as is supported by the results of the aforementioned meta-analysis).
  • Unknown frequency:
    • Anaemia.
    • Headache.
    • Increased respiratory rate.
    • Orthostatic hypotension.
    • Prolonged QT interval.
    • Visual disturbances.
  • Rare (<1% incidence):
    • Acute hepatic failure.
    • Agitation.
    • Agranulocytosis.
    • Anaphylactic reaction.
    • Anorexia.
    • Bronchospasm.
    • Cataracts.
    • Cholestasis.
    • Confusional state.
    • Depression.
    • Dermatitis exfoliative.
    • Dyspnoea.
    • Oedema.
    • Extrasystoles.
    • Face oedema.
    • Gynecomastia.
    • Hepatitis.
    • Hyperglycaemia.
    • Hypersensitivity.
    • Hyperthermia.
    • Hypoglycaemia.
    • Hyponatremia.
    • Hypothermia.
    • Increased sweating.
    • Injection site abscess.
    • Insomnia.
    • Itchiness.
    • Jaundice.
    • Laryngeal oedema.
    • Laryngospasm.
    • Leukocytoclastic vasculitis.
    • Leukopenia.
    • Liver function test abnormal.
    • Nausea.
    • Neuroleptic malignant syndrome.
    • Neutropenia.
    • Pancytopenia.
    • Photosensitivity reaction.
    • Priapism.
    • Psychotic disorder.
    • Pulmonary embolism.
    • Rash.
    • Retinopathy.
    • Seizure.
    • Sudden death.
    • Tardive dyskinesia.
    • Thrombocytopenia.
    • Torsades de pointes.
    • Urinary retention.
    • Urticaria.
    • Ventricular fibrillation.
    • Ventricular tachycardia.
    • Vomiting.

Contraindications

  • Pre-existing coma, acute stroke.
  • Severe intoxication with alcohol or other central depressant drugs.
  • Known allergy against haloperidol or other butyrophenones or other drug ingredients.
  • Known heart disease, when combined will tend towards cardiac arrest.

Special Cautions

  • A multiple-year study suggested this drug and other neuroleptic antipsychotic drugs commonly given to people with Alzheimer’s with mild behavioural problems often make their condition worse and its withdrawal was even beneficial for some cognitive and functional measures.
  • Elderly patients with dementia-related psychosis: analysis of 17 trials showed the risk of death in this group of patients was 1.6 to 1.7 times that of placebo-treated patients.
    • Most of the causes of death were either cardiovascular or infectious in nature.
    • It is not clear to what extent this observation is attributed to antipsychotic drugs rather than the characteristics of the patients.
    • The drug bears a boxed warning about this risk.
  • Impaired liver function, as haloperidol is metabolised and eliminated mainly by the liver.
  • In patients with hyperthyroidism, the action of haloperidol is intensified and side effects are more likely.
  • IV injections: risk of hypotension or orthostatic collapse.
  • Patients at special risk for the development of QT prolongation (hypokalaemia, concomitant use of other drugs causing QT prolongation).
  • Patients with a history of leukopenia: a complete blood count should be monitored frequently during the first few months of therapy and discontinuation of the drug should be considered at the first sign of a clinically significant decline in white blood cells.
  • Pre-existing Parkinson’s disease or dementia with Lewy bodies.

Interactions

  • Amiodarone: Q-Tc interval prolongation (potentially dangerous change in heart rhythm).
  • Amphetamine and methylphenidate: counteracts increased action of norepinephrine and dopamine in patients with narcolepsy or ADD/ADHD.
  • Epinephrine: action antagonised, paradoxical decrease in blood pressure may result.
  • Guanethidine: antihypertensive action antagonised.
  • Levodopa: decreased action of levodopa.
  • Lithium: rare cases of the following symptoms have been noted: encephalopathy, early and late extrapyramidal side effects, other neurologic symptoms, and coma.
  • Methyldopa: increased risk of extrapyramidal side effects and other unwanted central effects.
  • Other central depressants (alcohol, tranquilizers, narcotics): actions and side effects of these drugs (sedation, respiratory depression) are increased.
    • In particular, the doses of concomitantly used opioids for chronic pain can be reduced by 50%.
  • Other drugs metabolised by the CYP3A4 enzyme system: inducers such as carbamazepine, phenobarbital, and rifampicin decrease plasma levels and inhibitors such as quinidine, buspirone, and fluoxetine increase plasma levels.
  • Tricyclic antidepressants: metabolism and elimination of tricyclics significantly decreased, increased toxicity noted (anticholinergic and cardiovascular side effects, lowering of seizure threshold).

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.

Overdose

Symptoms

Symptoms are usually due to side effects. Most often encountered are:

  • Anticholinergic side effects (dry mouth, constipation, paralytic ileus, difficulties in urinating, decreased perspiration).
  • Coma in severe cases, accompanied by respiratory depression and massive hypotension, shock.
  • Hypotension or hypertension.
  • Rarely, serious ventricular arrhythmia (torsades de pointes), with or without prolonged QT-time.
  • Sedation.
  • Severe extrapyramidal side effects with muscle rigidity and tremors, akathisia, etc.

Treatment

Treatment is mostly symptomatic and involves intensive care with stabilisation of vital functions. In early detected cases of oral overdose, induction of emesis, gastric lavage, and the use of activated charcoal can be tried. In the case of a severe overdose, antidotes such as bromocriptine or ropinirole may be used to treat the extrapyramidal effects caused by haloperidol, acting as dopamine receptor agonists. ECG and vital signs should be monitored especially for QT prolongation and severe arrhythmias should be treated with antiarrhythmic measures.

Prognosis

In general, the prognosis of overdose is good, provided the person has survived the initial phase. An overdose of haloperidol can be fatal.

Pharmacology

Haloperidol is a typical butyrophenone type antipsychotic that exhibits high affinity dopamine D2 receptor antagonism and slow receptor dissociation kinetics. It has effects similar to the phenothiazines. The drug binds preferentially to D2 and α1 receptors at low dose (ED50 = 0.13 and 0.42 mg/kg, respectively), and 5-HT2 receptors at a higher dose (ED50 = 2.6 mg/kg). Given that antagonism of D2 receptors is more beneficial on the positive symptoms of schizophrenia and antagonism of 5-HT2 receptors on the negative symptoms, this characteristic underlies haloperidol’s greater effect on delusions, hallucinations and other manifestations of psychosis. Haloperidol’s negligible affinity for histamine H1 receptors and muscarinic M1 acetylcholine receptors yields an antipsychotic with a lower incidence of sedation, weight gain, and orthostatic hypotension though having higher rates of treatment emergent extrapyramidal symptoms.

Haloperidol acts on these receptors: (Ki)

  • D1 (silent antagonist) – Unknown efficiency.
  • D5 (silent antagonist) – Unknown efficiency.
  • D2 (inverse agonist) – 0.7 nM.
  • D3 (inverse agonist) – 0.2 nM.
  • D4 (inverse agonist) – 5–9 nM.
  • σ1 (irreversible inactivation by haloperidol metabolite HPP+) – 3 nM.
  • σ2 (agonist): 54 nM.
  • 5HT1A receptor agonist – 1927 nM.
  • 5HT2A (silent antagonist) – 53 nM.
  • 5HT2C (silent antagonist) – 10,000 nM.
  • 5HT6 (silent antagonist) – 3666 nM.
  • 5HT7 (irreversible silent antagonist) – 377.2 nM.
  • H1 (silent antagonist) – 1,800 nM.
  • M1 (silent antagonist) – 10,000 nM.
  • α1A (silent antagonist) – 12 nM.
  • α2A (silent antagonist) – 1130 nM.
  • α2B (silent antagonist) – 480 nM.
  • α2C (silent antagonist) – 550 nM.
  • NR1/NR2B subunit containing NMDA receptor (antagonist; ifenprodil site): IC50 – 2,000 nM.

Pharmacokinetics

By Mouth

The bioavailability of oral haloperidol ranges from 60-70%. However, there is a wide variance in reported mean Tmax and T1/2 in different studies, ranging from 1.7 to 6.1 hours and 14.5 to 36.7 hours respectively.

Intramuscular Injections

The drug is well and rapidly absorbed with a high bioavailability when injected intramuscularly. The Tmax is 20 minutes in healthy individuals and 33.8 minutes in patients with schizophrenia. The mean T1/2 is 20.7 hours. The decanoate injectable formulation is for intramuscular administration only and is not intended to be used intravenously. The plasma concentrations of haloperidol decanoate reach a peak at about six days after the injection, falling thereafter, with an approximate half-life of three weeks.

Intravenous Injections

The bioavailability is 100% in intravenous (IV) injection, and the very rapid onset of action is seen within seconds. The T1/2 is 14.1 to 26.2 hours. The apparent volume of distribution is between 9.5 and 21.7 L/kg. The duration of action is four to six hours.

Therapeutic Concentrations

Plasma levels of five to 15 micrograms per litre are typically seen for therapeutic response (Ulrich S, et al. Clin Pharmacokinet. 1998). The determination of plasma levels is rarely used to calculate dose adjustments but can be useful to check compliance.

The concentration of haloperidol in brain tissue is about 20-fold higher compared to blood levels. It is slowly eliminated from brain tissue, which may explain the slow disappearance of side effects when the medication is stopped.

Distribution and Metabolism

Haloperidol is heavily protein bound in human plasma, with a free fraction of only 7.5 to 11.6%. It is also extensively metabolised in the liver with only about 1% of the administered dose excreted unchanged in the urine. The greatest proportion of the hepatic clearance is by glucuronidation, followed by reduction and CYP-mediated oxidation, primarily by CYP3A4.

Society and Culture

Cost

Haloperidol is relatively inexpensive, being up to 100 fold less expensive than newer antipsychotics.

Brand Names

Haloperidol is the INN, BAN, USAN, AAN approved name.

It is sold under the tradenames Aloperidin, Bioperidolo, Brotopon, Dozic, Duraperidol (Germany), Einalon S, Eukystol, Haldol (common tradename in the US and UK), Halol, Halosten, Keselan, Linton, Peluces, Serenace and Sigaperidol.

Veterinary Use

Haloperidol is also used on many different kinds of animals for nonselective tranquilisation and diminishing behavioural arousal, in veterinary and other settings including captivity management.

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 a Typical Antipsychotic?

Introduction

Typical antipsychotics (also known as major tranquilisers, or first generation antipsychotics) are a class of antipsychotic drugs first developed in the 1950s and used to treat psychosis (in particular, schizophrenia).

Advertisement for Thorazine (chlorpromazine) from the 1950s, reflecting the perceptions of psychosis, including the now-discredited perception of a tendency towards violence, from the time when antipsychotics were discovered.

Typical antipsychotics may also be used for the treatment of acute mania, agitation, and other conditions. The first typical antipsychotics to come into medical use were the phenothiazines, namely chlorpromazine which was discovered serendipitously. Another prominent grouping of antipsychotics are the butyrophenones, an example of which is haloperidol. The newer, second-generation antipsychotics, also known as atypical antipsychotics, have largely supplanted the use of typical antipsychotics as first-line agents due to the higher risk of movement disorders in the latter.

Both generations of medication tend to block receptors in the brain’s dopamine pathways, but atypicals at the time of marketing were claimed to differ from typical antipsychotics in that they are less likely to cause extrapyramidal symptoms (EPS), which include unsteady Parkinson’s disease-type movements, internal restlessness, and other involuntary movements (e.g. tardive dyskinesia, which can persist after stopping the medication). More recent research has demonstrated the side effect profile of these drugs is similar to older drugs, causing the leading medical journal The Lancet to write in its editorial “the time has come to abandon the terms first-generation and second-generation antipsychotics, as they do not merit this distinction.” While typical antipsychotics are more likely to cause EPS, atypicals are more likely to cause adverse metabolic effects, such as weight gain and increase the risk for type II diabetes.

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 after an initial report in 1952. It was first used in psychiatric institutions because of its powerful tranquilising effect; at the time it was regarded as a non-permanent “pharmacological lobotomy” (Note that “tranquilizing” here only refers to changes in external behaviour, while the experience a person has internally may be one of increased agitation but inability to express it).

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 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 effects such as reduced activity in general, as well as lethargy and impaired motor control. Although these effects are unpleasant and harmful, they were, along with akathisia, considered a reliable sign that the drug was working. These terms have been largely replaced by the term “antipsychotic” in medical and advertising literature, which refers to the medication’s more-marketable effects.

Clinical Uses

Typical antipsychotics block the dopamine 2 receptor (D2) receptor, causing a tranquilising effect. It is thought that 60-80% of D2 receptors need to be occupied for antipsychotic effect. For reference, the typical antipsychotic haloperidol tends to block about 80% of D2 receptors at doses ranging from 2 to 5 mg per day. On the aggregate level, no typical antipsychotic is more effective than any other, though people will vary in which antipsychotic they prefer to take (based on individual differences in tolerability and effectiveness). Typical antipsychotics can be used to treat, e.g. schizophrenia or severe agitation. Haloperidol, due to the availability of a rapid-acting injectable formulation and decades of use, remains the most commonly used tranquilizer for chemical restraint in the emergency department setting (in the interests of hospital staff, not to meet a medical need of the patient).

Adverse Effects

Adverse effects vary among the various agents in this class of medications, but common effects include: dry mouth, muscle stiffness, muscle cramping, tremors, EPS and weight gain. EPS refers to a cluster of symptoms consisting of akathisia, parkinsonism, and dystonia. Anticholinergics such as benztropine and diphenhydramine are commonly prescribed to treat the EPS. 4% of users develop rabbit syndrome while on typical antipsychotics.

There is a risk of developing a serious condition called tardive dyskinesia as a side effect of antipsychotics, including typical antipsychotics. The risk of developing tardive dyskinesia after chronic typical antipsychotic usage varies on several factors, such as age and gender, as well as the specific antipsychotic used. The commonly reported incidence of TD among younger patients is about 5% per year. Among older patients incidence rates as high as 20% per year have been reported. The average prevalence is approximately 30%. There are few treatments that have consistently been shown to be effective for the treatment of tardive dyskinesia, though an VMAT2 inhibitor like valbenazine may help. The atypical antipsychotic clozapine has also been suggested as an alternative antipsychotic for patients experiencing tardive dyskinesia. Tardive dyskinesia may reverse upon discontinuation of the offending agent or it may be irreversible, withdrawal may also make tardive dyskinesia more severe.

Neuroleptic malignant syndrome, or NMS, is a rare, but potentially fatal side effect of antipsychotic treatment. NMS is characterized by fever, muscle rigidity, autonomic dysfunction, and altered mental status. Treatment includes discontinuation of the offending agent and supportive care.

The role of typical antipsychotics has come into question recently as studies have suggested that typical antipsychotics may increase the risk of death in elderly patients. A retrospective cohort study from the New England Journal of Medicine on 01 December 2005 showed an increase in risk of death with the use of typical antipsychotics that was on par with the increase shown with atypical antipsychotics. This has led some to question the common use of antipsychotics for the treatment of agitation in the elderly, particularly with the availability of alternatives such as mood stabilising and antiepileptic drugs.

Potency

Traditional antipsychotics are classified as high-potency, mid-potency, or low-potency based on their potency for the D2 receptor as noted in the table below.

PotencyExamplesAdverse Effect Profile
HighFluphenazine and HaloperidolMore extrapyramidal side effects (EPS) and less antihistaminic effects (e.g. sedation), alpha adrenergic antagonism (e.g. orthostatic hypotension), and anticholinergic effects (e.g. dry mouth).
MediumPerphenazine and LoxapineIntermediate D2 affinity, with more off-target effects than high-potency agents.
LowChlorpromazineLess risk of EPS but more antihistaminic effects, alpha adrenergic antagonism, and anticholinergic effects.

Prochlorperazine (Compazine, Buccastem, Stemetil) and Pimozide (Orap) are less commonly used to treat psychotic states, and so are sometimes excluded from this classification.

A related concept to D2 potency is the concept of “chlorpromazine equivalence”, which provides a measure of the relative effectiveness of antipsychotics. The measure specifies the amount (mass) in milligrams of a given drug that must be administered in order to achieve desired effects equivalent to those of 100 milligrams of chlorpromazine. Another method is “defined daily dose” (DDD), which is the assumed average dose of an antipsychotic that an adult would receive during long-term treatment. DDD is primarily used for comparing the utilization of antipsychotics (e.g. in an insurance claim database), rather than comparing therapeutic effects between antipsychotics. Maximum dose methods are sometimes used to compare between antipsychotics as well. It is important to note that these methods do not generally account for differences between the tolerability (i.e. the risk of side effects) or the safety between medications.

Below is list of typical antipsychotics organised by potency.

  • Low potency:
    • Chlorpromazine.
    • Chlorprothixene.
    • Levomepromazine.
    • Mesoridazine.
    • Periciazine.
    • Promazine.
    • Thioridazine (withdrawn by brand-name manufacturer and most countries, and since discontinued).
  • Medium potency:
    • Loxapine.
    • Molindone.
    • Perphenazine.
    • Thiothixene.
  • High potency:
    • Droperidol.
    • Flupentixol.
    • Fluphenazine.
    • Haloperidol.
    • Pimozide.
    • Prochlorperazine.
    • Thioproperazine.
    • Trifluoperazine.
    • Zuclopenthixol.

Long-Acting Injectables

Some typical antipsychotics have been formulated as a long-acting injectable (LAI), or “depot”, formulation. Depot injections are also used on persons under involuntary commitment to force compliance with a court treatment order when the person would refuse to take daily oral medication. This has the effect of dosing a person who doesn’t consent to take the drug. The United Nations Special Rapporteur On Torture has classified this as a human rights violation and cruel or inhuman treatment.

The first LAI antipsychotics (often referred to as simply “LAIs”) were the typical antipsychotics fluphenazine and haloperidol. Both fluphenazile and haloperidol are formulated as decanoates, referring to the attachment of a decanoic acid group to the antipsychotic molecule. These are then dissolved in an organic oil. Together, these modifications prevent the active medications from being released immediately upon injection, attaining a slow release of the active medications (note, though, that the fluphenazine decanoate product is unique for reaching peak fluphenazine blood levels within 24 hours after administration). Fluphenazine decanoate can be administered every 7 to 21 days (usually every 14 to 28 days), while haloperidol decanoate can be administered every 28 days, though some people receive more or less frequent injections. If a scheduled injection of either haloperidol decanoate or fluphenazine decanoate is missed, recommendations for administering make-up injectable dose(s) or providing antipsychotics to be taken by mouth vary by, e.g. how long ago the last injection was and how many previous injections the person has received (i.e. if steady state levels of the medication have been reached or not).

Both of the typical antipsychotic LAIs are inexpensive in comparison to the atypical LAIs. Doctors usually prefer atypical LAIs over typical LAIs due to the differences in adverse effects between typical and atypical antipsychotics in general.

What is Thioridazine?

Introduction

Thioridazine (Mellaril or Melleril) is a first generation antipsychotic drug belonging to the phenothiazine drug group and was previously widely used in the treatment of schizophrenia and psychosis.

The branded product was withdrawn worldwide in 2005 because it caused severe cardiac arrhythmias. However, generic versions are still available in the US.

Brief History

The manufacturer Novartis/Sandoz/Wander of the brands of thioridazine, Mellaril in the US and Canada and Melleril in Europe, discontinued the drug worldwide in June 2005.

Indications

Thioridazine was voluntarily discontinued by its manufacturer, Novartis, worldwide because it caused severe cardiac arrhythmias.

Its primary use in medicine was the treatment of schizophrenia. It was also tried with some success as a treatment for various psychiatric symptoms seen in people with dementia, but chronic use of thioridazine and other anti-psychotics in people with dementia is not recommended.

Side Effects

Thioridazine prolongs the QTc interval in a dose-dependent manner. It produces significantly less extrapyramidal side effects than most first-generation antipsychotics. Its use, along with the use of other typical antipsychotics, has been associated with degenerative retinopathies. It has a higher propensity for causing anticholinergic side effects coupled with a lower propensity for causing extrapyramidal side effects and sedation than chlorpromazine, but also has a higher incidence of hypotension and cardiotoxicity. It is also known to possess a relatively high liability for causing orthostatic hypotension compared to other antipsychotics. Similarly to other first-generation antipsychotics it has a relatively high liability for causing prolactin elevation. It is moderate risk for causing weight gain. As with all antipsychotics thioridazine has been linked to cases of tardive dyskinesia (an often permanent neurological disorder characterised by slow, repetitive, purposeless and involuntary movements, most often of the facial muscles, that is usually brought on by years of continued treatment with antipsychotics, especially the first-generation (or typical) antipsychotics such as thioridazine) and neuroleptic malignant syndrome (a potentially fatal complication of antipsychotic treatment). Blood dyscrasias such as agranulocytosis, leukopenia and neutropenia are possible with thioridazine treatment. Thioridazine is also associated with abnormal retinal pigmentation after many years of use. Thioridazine has been correlated to rare instances of clinically apparent acute cholestatic liver injury.

Metabolism

Thioridazine is a racemic compound with two enantiomers, both of which are metabolised, according to Eap et al., by CYP2D6 into (S)- and (R)-thioridazine-2-sulfoxide, better known as mesoridazine, and into (S)- and (R)-thioridazine-5-sulfoxide. Mesoridazine is in turn metabolized into sulforidazine. Thioridazine is an inhibitor of CYP1A2 and CYP3A4.

Antibiotic Activity

Thioridazine is known to kill extensively drug-resistant tuberculosis and to make methicillin-resistant Staphylococcus aureus sensitive to β-lactam antibiotics. A possible mechanism of action for the drug’s antibiotic activity is via the inhibition of bacterial secretion pumps. The β-lactam antibiotic resistance is due to the secretion β-lactamase a protein that destroys antibiotics. If the bacteria cannot secrete the β-lactamase, then the antibiotic will be effective.

What is Trifluoperazine?

Introduction

Trifluoperazine, sold under a number of brand names, is a typical antipsychotic primarily used to treat schizophrenia.

It may also be used short term in those with generalised anxiety disorder but is less preferred to benzodiazepines. It is of the phenothiazine chemical class.

Medical Uses

Schizophrenia

Trifluoperazine is an effective antipsychotic for people with schizophrenia. There is low-quality evidence that trifluoperazine increases the chance of being improved when compared to placebo when people are followed up for 19 weeks. There is low-quality evidence that trifluoperazine reduces the risk of relapse when compared with placebo when people are followed for 5 months. As of 2014 there was no good evidence for a difference between trifluoperazine and placebo with respect to the risk of experiencing intensified symptoms over a 16-week period nor in reducing significant agitation or distress.

There is no good evidence that trifluoperazine is more effective for schizophrenia than lower-potency antipsychotics like chlorpromazine, chlorprothixene, thioridazine and levomepromazine, but trifluoperazine appears to cause more adverse effects than these drugs.

Other

It appears to be effective for people with generalised anxiety disorder but the benefit-risk ratio was unclear as of 2005.

It has been experimentally used as a drug to kill eukaryotic pathogens in humans.

Side Effects

Its use in many parts of the world has declined because of highly frequent and severe early and late tardive dyskinesia, a type of extrapyramidal symptom. The annual development rate of tardive dyskinesia may be as high as 4%.

A 2004 meta-analysis of the studies on trifluoperazine found that it is more likely than placebo to cause extrapyramidal side effects such as akathisia, dystonia, and Parkinsonism. It is also more likely to cause somnolence and anticholinergic side effects such as red eye and xerostomia (dry mouth). All antipsychotics can cause the rare and sometimes fatal neuroleptic malignant syndrome. Trifluoperazine can lower the seizure threshold. The antimuscarinic action of trifluoperazine can cause excessive dilation of the pupils (mydriasis), which increases the chances of patients with hyperopia developing glaucoma.

Contraindications

Trifluoperazine is contraindicated in CNS depression, coma, and blood dyscrasias. Trifluoperazine should be used with caution in patients suffering from renal or hepatic impairment.

Mechanism of Action

Trifluoperazine has central antiadrenergic, antidopaminergic, and minimal anticholinergic effects. It is believed to work by blockading dopamine D1 and D2 receptors in the mesocortical and mesolimbic pathways, relieving or minimising such symptoms of schizophrenia as hallucinations, delusions, and disorganised thought and speech.

Names

Brand names include Eskazinyl, Eskazine, Jatroneural, Modalina, Stelazine, Stilizan, Terfluzine, Trifluoperaz, Triftazin.

In the United Kingdom and some other countries, trifluoperazine is sold and marketed under the brand ‘Stelazine’.

The drug is sold as tablet, liquid and ‘Trifluoperazine-injectable USP’ for deep intramuscular short-term use. GP studying pharmacological data has indicated cases of neck vertebrae irreversible fusing leading to NHS preparations being predominantly of the liquid form trifluoperazine as opposed to the tablet form as in Stela zine etc.

In the past, trifluoperazine was used in fixed combinations with the MAO inhibitor (antidepressant) tranylcypromine (tranylcypromine/trifluoperazine) to attenuate the strong stimulating effects of this antidepressant. This combination was sold under the brand name Jatrosom N. Likewise a combination with amobarbital (potent sedative/hypnotic agent) for the amelioration of psychoneurosis and insomnia existed under the brand name Jalonac. In Italy the first combination is still available, sold under the brand name Parmodalin (10 mg of tranylcypromine and 1 mg of trifluoperazine).

What is Zuclopenthixol?

Introduction

Zuclopenthixol (brand names Cisordinol, Clopixol and others), also known as zuclopentixol, is a medication used to treat schizophrenia and other psychoses.

It is classed, pharmacologically, as a typical antipsychotic. Chemically it is a thioxanthene. It is the cis-isomer of clopenthixol (Sordinol, Ciatyl). Clopenthixol was introduced in 1961, while zuclopenthixol was introduced in 1978.

Zuclopenthixol is a D1 and D2 antagonist, α1-adrenergic and 5-HT2 antagonist. While it is approved for use in Australia, Canada, Ireland, India, New Zealand, Singapore, South Africa and the UK it is not approved for use in the United States.

Brief History

Zuclopenthixol was introduced by Lundbeck in 1978.

Medical Uses

Available Forms

Zuclopenthixol is available in three major preparations:

  1. As zuclopenthixol decanoate (Clopixol Depot, Cisordinol Depot), it is a long-acting intramuscular (IM) injection.
    1. Its main use is as a long-acting injection given every two or three weeks to people with schizophrenia who have a poor compliance with medication and suffer frequent relapses of illness.
    2. There is some evidence it may be more helpful in managing aggressive behaviour.
  2. As zuclopenthixol acetate (Clopixol-Acuphase, Cisordinol-Acutard), it is a shorter-acting intramuscular injection used in the acute sedation of psychotic inpatients.
    1. The effect peaks at 48-72 hours providing 2-3 days of sedation.
  3. As zuclopenthixol dihydrochloride (Clopixol, Cisordinol), it is a tablet used in the treatment of schizophrenia in those who are compliant with oral medication.

It is also used in the treatment of acute bipolar mania.

Dosing

As a long-acting injection, zuclopenthixol decanoate comes in a 200 mg and 500 mg ampoule. Doses can vary from 50 mg weekly to the maximum licensed dose of 600 mg weekly. In general, the lowest effective dose to prevent relapse is preferred. The interval may be shorter as a patient starts on the medication before extending to 3 weekly intervals subsequently. The dose should be reviewed and reduced if side effects occur, though in the short-term an anticholinergic medication benztropine may be helpful for tremor and stiffness, while diazepam may be helpful for akathisia. 100 mg of zuclopenthixol decanoate is roughly equivalent to 20 mg of flupentixol decanoate or 12.5 mg of fluphenazine decanoate.

In acutely psychotic and agitated inpatients, 50-200 mg of zuclopenthixol acetate may be given for a calming effect over the subsequent three days, with a maximum dose of 400 mg in total to be given. As it is a long-acting medication, care must be taken not to give an excessive dose.

In oral form zuclopenthixol is available in 10, 25 and 40 mg tablets, with a dose range of 20-60 mg daily.

Side Effects

Chronic administration of zuclopenthixol (30 mg/kg/day for two years) in rats resulted in small, but significant, increases in the incidence of thyroid parafollicular carcinomas and, in females, of mammary adenocarcinomas and of pancreatic islet cell adenomas and carcinomas. An increase in the incidence of mammary adenocarcinomas is a common finding for D2 antagonists which increase prolactin secretion when administered to rats. An increase in the incidence of pancreatic islet cell tumours has been observed for some other D2 antagonists. The physiological differences between rats and humans with regard to prolactin make the clinical significance of these findings unclear.

Withdrawal syndrome: Abrupt cessation of therapy may cause acute withdrawal symptoms (eg, nausea, vomiting, or insomnia). Symptoms usually begin in 1 to 4 days of withdrawal and subside within 1 to 2 weeks.

Other permanent side effects are similar to many other typical antipsychotics, namely extrapyramidal symptoms as a result of dopamine blockade in subcortical areas of the brain. This may result in symptoms similar to those seen in Parkinson’s disease and include a restlessness and inability to sit still known as akathisia, a slow tremor and stiffness of the limbs. Zuclopenthixol is thought to be more sedating than the related flupentixol, though possibly less likely to induce extrapyramidal symptoms than other typical depots. As with other dopamine antagonists, zuclopenthixol may sometimes elevate prolactin levels; this may occasionally result in amenorrhoea or galactorrhoea in severe cases. Neuroleptic malignant syndrome is a rare but potentially fatal side effect. Any unexpected deterioration in mental state with confusion and muscle stiffness should be seen by a physician.

Zuclopenthixol decanoate induces a transient dose-dependent sedation. However, if the patient is switched to maintenance treatment with zuclopenthixol decanoate from oral zuclopenthixol or from IM zuclopenthixol acetate the sedation will be no problem. Tolerance to the unspecific sedative effect develops rapidly.

  • Very common Adverse Effects (≥10% incidence):
    • Dry Mouth.
    • Somnolence.
    • Akathisia.
    • Hyperkinesia.
    • Hypokinesia.
  • Common (1%≤incidence≤10%):
    • Tachycardia.
    • Palpitations.
    • Vertigo.
    • Accommodation disorder.
    • Vision abnormal.
    • Salivary hypersecretion.
    • Constipation.
    • Vomiting.
    • Dyspepsia.
    • Diarrhoea.
    • Asthenia.
    • Fatigue.
    • Malaise.
    • Pain (at the injection site).
    • Increased appetite.
    • Weight gain.
    • Myalgia.
    • Tremor.
    • Dystonia.
    • Hypertonia.
    • Dizziness.
    • Headache.
    • Paraesthesia.
    • Disturbance in attention.
    • Amnesia.
    • Gait abnormal.
    • Insomnia.
    • Depression.
    • Anxiety.
    • Nervousness.
    • Abnormal dreams.
    • Agitation.
    • Libido decreased.
    • Nasal congestion.
    • Dyspnoea.
    • Hyperhidrosis.
    • Pruritus.
  • Uncommon (0.1%≤incidence≤1%):
    • Hyperacusis.
    • Tinnitus.
    • Oculogyration.
    • Mydriasis.
    • Abdominal pain.
    • Nausea.
    • Flatulence.
    • Thirst.
    • Injection site reaction.
    • Hypothermia.
    • Pyrexia.
    • Liver function test abnormal.
    • Decreased appetite.
    • Weight loss.
    • Muscle rigidity.
    • Trismus.
    • Torticollis.
    • Tardive dyskinesia.
    • Hyperreflexia.
    • Dyskinesia.
    • Parkinsonism.
    • Syncope.
    • Ataxia.
    • Speech disorder.
    • Hypotonia.
    • Convulsion.
    • Migraine.
    • Apathy.
    • Nightmare.
    • Libido increased.
    • Confusional state.
    • Ejaculation failure.
    • Erectile dysfunction.
    • Female orgasmic disorder.
    • Vulvovaginal.
    • Dryness.
    • Rash.
    • Photosensitivity reaction.
    • Pigmentation disorder.
    • Seborrhoea.
    • Dermatitis.
    • Purpura.
    • Hypotension.
    • Hot flush.
  • Rare (0.01%≤incidence≤0.1%):
    • Thrombocytopenia.
    • Neutropenia.
    • Leukopenia.
    • Agranulocytosis.
    • Electrocardiogram QT prolonged.
    • Hyperprolactinaemia.
    • Hypersensitivity.
    • Anaphylactic reaction.
    • Hyperglycaemia.
    • Glucose tolerance impaired.
    • Hyperlipidaemia.
    • Gynaecomastia.
    • Galactorrhoea.
    • Amenorrhoea.
    • Priapism.
    • Withdrawal symptoms.
  • Very rare (incidence<0.01%):
    • Cholestatic hepatitis.
    • Jaundice.
    • Neuroleptic malignant syndrome.
    • Venous thromboembolism.

Pharmacology

Pharmacodynamics

Zuclopenthixol antagonises both dopamine D1 and D2 receptors, α1-adrenoceptors and 5-HT2 receptors with a high affinity, but has no affinity for cholinergic muscarine receptors. It weakly antagonises the histamine (H1) receptor but has no α2-adrenoceptor blocking activity.

Evidence from in vitro work and clinical sources (i.e. therapeutic drug monitoring databases) suggests that both CYP2D6 and CYP3A4 play important roles in zuclopenthixol metabolism.

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.