What is the Texas Medication Algorithm Project?

Introduction

The Texas Medication Algorithm Project (TMAP) is a controversial decision-tree medical algorithm, the design of which was based on the expert opinions of mental health specialists.

It has provided and rolled out a set of psychiatric management guidelines for doctors treating certain mental disorders within Texas’ publicly funded mental health care system, along with manuals relating to each of them. The algorithms commence after diagnosis and cover pharmacological treatment (hence “Medication Algorithm”).

Brief History

TMAP was initiated in the fall (winter) of 1997 and the initial research covered around 500 patients.

TMAP arose from a collaboration that began in 1995 between the Texas Department of Mental Health and Mental Retardation (TDMHMR), pharmaceutical companies, and the University of Texas Southwestern. The research was supported by the National Institute of Mental Health, the Robert Wood Johnson Foundation, the Meadows Foundation, the Lightner-Sams Foundation, the Nanny Hogan Boyd Charitable Trust, TDMHMR, the Centre for Mental Health Services, the Department of Veterans Affairs, the Health Services Research and Development Research Career Scientist Award, the United States Pharmacopoeia Convention Inc. and Mental Health Connections.

Numerous companies that invent and develop antipsychotic medications provided use of their medications and furnished funding for the project. Companies did not participate in the production of the guidelines.

In 2004 TMAP was mentioned as an example of a successful project in a paper regarding implementing mental health screening programmes throughout the United States, by the President George W. Bush’s New Freedom Commission on Mental Health, which looks to expand the programme federally. The President had previously been Governor of Texas, in the period when TMAP was implemented. Similar programmes have been implemented in about a dozen States, according to a 2004 report in the British Medical Journal.

Similar algorithms with similar prescribing advice have been produced elsewhere, for instance at the Maudsley Hospital, London.

What is Barbiturate Dependence?

Introduction

Barbiturate dependence develops with regular use of barbiturates. This in turn may lead to a need for increasing doses of the drug to get the original desired pharmacological or therapeutic effect.

Refer to Barbiturate Overdose.

Background

Barbiturate use can lead to both addiction and physical dependence, and as such they have a high potential for excess or non-medical use, however, it does not affect all users. Management of barbiturate dependence involves considering the affected person’s age, comorbidity and the pharmacological pathways of barbiturates.

Psychological addiction to barbiturates can develop quickly. The patients will then have a strong desire to take any barbiturate-like drug. The chronic use of barbiturates leads to moderate degradation of the personality with narrowing of interests, passivity and loss of volition. The somatic signs include hypomimia, problems articulating, weakening of reflexes, and ataxia.

The GABAA receptor, one of barbiturates’ main sites of action, is thought to play a pivotal role in the development of tolerance to and dependence on barbiturates, as well as the euphoric “high” that results from their use. The mechanism by which barbiturate tolerance develops is believed to be different from that of ethanol or benzodiazepines, even though these drugs have been shown to exhibit cross-tolerance with each other and poly drug administration of barbiturates and alcohol used to be common.

The management of a physical dependence on barbiturates is stabilisation on the long-acting barbiturate phenobarbital followed by a gradual titration down of dose. People who use barbiturates tend to prefer rapid-acting barbiturates (amobarbital, pentobarbital, secobarbital) rather than long-acting barbiturates (barbital, phenobarbital). The slowly eliminated phenobarbital lessens the severity of the withdrawal syndrome and reduces the chances of serious barbiturate withdrawal effects such as seizures. A cold turkey withdrawal can in some cases lead to death. Antipsychotics are not recommended for barbiturate withdrawal (or other CNS depressant withdrawal states) especially clozapine, olanzapine or low potency phenothiazines e.g. chlorpromazine as they lower the seizure threshold and can worsen withdrawal effects; if used extreme caution is required. The withdrawal symptoms after ending barbiturate consumption are quite severe and last from 4 to 7 days.

What is a Paradoxical Reaction?

Introduction

A paradoxical reaction or paradoxical effect is an effect of a chemical substance, typically a medical drug, that is opposite to what would usually be expected. An example of a paradoxical reaction is pain caused by a pain relief medication.

Paradoxical reactions are more commonly observed in people with attention deficit hyperactivity disorder (ADHD).

Substances

Amphetamines

Amphetamines are a class of psychoactive drugs that are stimulants. Paradoxical drowsiness can sometimes occur in adults.

Antibiotics

The paradoxical effect or Eagle effect (named after H. Eagle who first described it) refers to an observation of an increase in survivors, seen when testing the activity of an antimicrobial agent. Initially when an antibiotic agent is added to a culture media, the number of bacteria that survive drops, as one would expect. But after increasing the concentration beyond a certain point, the number of bacteria that survive, paradoxically, increases.

Antidepressants

In rare cases antidepressants can make users obsessively violent or have suicidal compulsions, which is in marked contrast to their intended effect. This can be regarded as a paradoxical reaction but, especially in the case of suicide, may in at least some cases be merely due to differing rates of effect with respect to different symptoms of depression: If generalised overinhibition of a patient’s actions enters remission before that patient’s dysphoria does and if the patient was already suicidal but too depressed to act on their inclinations, the patient may find themselves in the situation of being both still dysphoric enough to want to commit suicide but newly free of endogenous barriers against doing so. Children and adolescents are more sensitive to paradoxical reactions of self-harm and suicidal ideation while taking antidepressants but cases are still very rare.

Antipsychotics

Chlorpromazine, an antipsychotic and antiemetic drug, which is classed as a “major” tranquilizer may cause paradoxical effects such as agitation, excitement, insomnia, bizarre dreams, aggravation of psychotic symptoms and toxic confusional states.

Barbiturates

Phenobarbital can cause hyperactivity in children. This may follow after a small dose of 20 mg, on condition of no phenobarbital administered in previous days. Prerequisity for this reaction is a continued sense of tension. The mechanism of action is not known, but it may be started by the anxiolytic action of the phenobarbital.

Benzodiazepines

Benzodiazepines, a class of psychoactive drugs called the “minor” tranquilisers, have varying hypnotic, sedative, anxiolytic, anticonvulsant, and muscle relaxing properties, but they may create the exact opposite effects. Susceptible individuals may respond to benzodiazepine treatment with an increase in anxiety, aggressiveness, agitation, confusion, disinhibition, loss of impulse control, talkativeness, violent behaviour, and even convulsions. Paradoxical adverse effects may even lead to criminal behaviour. Severe behavioural changes resulting from benzodiazepines have been reported including mania, schizophrenia, anger, impulsivity, and hypomania.

Paradoxical rage reactions due to benzodiazepines occur as a result of an altered level of consciousness, which generates automatic behaviours, anterograde amnesia and uninhibited aggression. These aggressive reactions may be caused by a disinhibiting serotonergic mechanism.

Paradoxical effects of benzodiazepines appear to be dose related, that is, likelier to occur with higher doses.

In a letter to the British Medical Journal, it was reported that a high proportion of parents referred for actual or threatened child abuse were taking medication at the time, often a combination of benzodiazepines and tricyclic antidepressants. Many mothers described that instead of feeling less anxious or depressed, they became more hostile and openly aggressive towards the child as well as to other family members while consuming tranquilizers. The author warned that environmental or social stresses such as difficulty coping with a crying baby combined with the effects of tranquilisers may precipitate a child abuse event.

Self aggression has been reported and also demonstrated in laboratory conditions in a clinical study. Diazepam was found to increase people’s willingness to harm themselves.

Benzodiazepines can sometimes cause a paradoxical worsening of EEG readings in patients with seizure disorders.

Barbiturates such as pentobarbital have been shown to cause paradoxical hyperactivity in an estimated 1% of children, who display symptoms similar to the hyperactive-impulsive subtype of attention deficit hyperactivity disorder. Intravenous caffeine administration can return these patients’ behaviour to baseline levels.

Causes

The mechanism of a paradoxical reaction has as yet (2019) not been fully clarified, in no small part due to the fact that signal transfer of single neurons in subcortical areas of the human brain is usually not accessible.

There are, however, multiple indications that paradoxical reactions upon – for example – benzodiazepines, barbiturates, inhalational anaesthetics, propofol, neurosteroids, and alcohol are associated with structural deviations of GABAA receptors. The combination of the five subunits of the receptor (see image) can be altered in such a way that for example the receptor’s response to GABA remains unchanged but the response to one of the named substances is dramatically different from the normal one.

There are estimates that about 2-3% of the general population may suffer from serious emotional disorders due to such receptor deviations, with up to 20% suffering from moderate disorders of this kind. It is generally assumed that the receptor alterations are, at least partly, due to genetic and also epigenetic deviations. There are indication that the latter may be triggered by, among other factors, social stress or occupational burnout.

What are the Adverse Effects of Olanzpine?

Introduction

Below is a list of the adverse effects of the antipsychotic olanzapine, sorted by frequency of occurrence.

Very Common

Very common adverse effects of olanzapine, occurring more than 10%, include:

  • Weight gain (dose-dependent).
    • Weight gain of over 7% of a person’s initial body weight prior to treatment is in this category of very common too with some estimates of its incidence putting it at around 40.6%.
    • This adverse effect is most likely the result of its potent 5-HT2C receptor and H1 receptor blockade (or more specifically inverse agonism).
  • Somnolence (dose-dependent).
    • Tends to produce a moderate amount of sedation, less than clozapine and chlorpromazine but more than aripiprazole, amisulpride, paliperidone and sertindole and approximately that of quetiapine and risperidone.
  • Hyperprolactinemia elevated blood levels of the hormone, prolactin.
    • Prolactin is one of the hormones that plays a key role in lactation. Long-term uncontrolled hyperprolactinaemia can lead to bone demineralisation (osteoporosis) and an increased risk of fractures (breaks).
    • It tends to produce hyperlacticaemia less often than risperidone, paliperidone and the typical antipsychotics but more often than quetiapine and clozapine.
  • Hypertriglyceridaemia (elevated blood triglycerides).
  • Hypercholesterolaemia (elevated blood cholesterol levels).
  • Hyperglycaemia (elevated blood glucose levels).
    • This may be the result of olanzapine’s inhibitory effects on the M3 receptor which regulates the release of insulin from the pancreas.
  • Brain shrinkage (dose dependent).

Common

Common adverse effects of olanzapine, occurring from 1-10%, include:

  • Gynecomastia.
  • Extrapyramidal symptoms (EPS) (dose-dependent).
    • Tends to produce less extrapyramidal side effects than typical antipsychotics but more extrapyramidal side effects than sertindole, clozapine and quetiapine.
  • Mild and transient constipation and xerostomia (dry mouth).
  • Dizziness.
  • Weight gain of over 15% of one’s initial body weight.
    • Is reported to occur in approximately 7.1% of patients.
  • Glucosuria (glucose in the urine).
    • This is a consequence of hyperglycaemia.
  • Accidental injury.
  • Insomnia.
  • Orthostatic hypotension (a drop in blood pressure that occurs upon standing up).
  • Transient, asymptomatic elevations of hepatic aminotransferases (ALT, AST), especially in early treatment.
    • ALT & AST are liver enzymes which are often tested for as a measure of liver function.
  • Dyspepsia (indigestion).
  • Erectile dysfunction.
    • This is most likely the result of hyperprolactinaemia.
  • Decreased libido.
    • This is most likely the result of hyperprolactinaemia.
  • Rash.
  • Asthenia (weakness).
  • Fatigue.
  • Oedema the accumulation of fluid in the tissues of the body leading to swelling.
  • Akathisia an inner sense of restlessness that presents itself with the inability to stay still.
  • Parkinsonism tremor, muscle rigidity, reduced ability to move and being unstable on one’s feet.
  • Dyskinesia abnormal, involuntary, repetitive, and pointless movements.
  • Vomiting.
  • Coma.
  • Cardiac arrest.

Uncommon

Uncommon adverse effects of olanzapine, occurring from 0.1-1%, include:

  • Leukopenia a comparatively low white blood cell (the cells that defend the body from foreign invaders) count.
  • Neutropaenia a reduced neutrophil (the white blood cells that kill bacteria) count.
  • Bradycardia (low heart rate).
  • QTc interval prolongation (an abnormality in the electrical cycle of the heart).
  • Photosensitivity reaction.
  • Alopecia (hair loss).
  • Urinary incontinence.
  • Urinary retention, the inability to urinate.
  • Amenorrhea the cessation of menses (a woman’s menstrual cycles).
    • This is a complication of hyperprolactinaemia.
  • Breast enlargement (in either sex).
    • This is a complication of hyperprolactinaemia.
  • Galactorrhoea (expulsion of milk from the breasts that’s unrelated to pregnancy or lactation).
    • Most likely the result of hyperprolactinaemia.
  • High creatine phosphokinase (an abnormal laboratory finding).
  • Increased total bilirubin (a by product of the breakdown of haem – a part of blood cells that is used to carry oxygen).
    • In most people this is an indication of impaired liver function.
  • Abdominal pain.

Rare

Rare adverse effects of olanzapine, occurring from 0.01-0.1%, include:

  • Hepatitis.
  • Rash.
  • Seizures.
  • Glaucoma.
  • Blindness.

Very Rare (But Not Necessarily Causally Related)

Very rare adverse effects of olanzapine, occurring less than 0.01%, include:

  • Agranulocytosis, a potentially fatal drop in white blood cell count, basically an exaggerated form of leukopenia.
  • Thrombocytopaenia.
    • A drop in blood platelet counts which are involved in blood clotting.
  • Thromboembolism (blood clots; including pulmonary embolism and deep vein thrombosis).
  • Rhabdomyolysis (breakdown of muscle tissue leading to the release of myoglobin into the bloodstream which in turn damages the kidneys).
  • Alkaline phosphatase increased (an abnormal laboratory parameter).
  • Priapism (a painful and enduring erection).
  • Urinary hesitation.
  • Pancreatitis, swelling of the pancreas which supplies the body with insulin.
  • Neuroleptic malignant syndrome a potentially fatal complication of antipsychotic drug treatment.
    • Presents with hyperthermia, tremor, tachycardia (high heart rate), mental status change (e.g. confusion), etc.
  • Jaundice, which is basically when the body’s ability to clear a by product (called bilirubin) of the breakdown of an essential component of the blood called haem, is impaired leading to yellow discolouration of the skin, eyes and mucous membranes.
  • Diabetic coma.
  • Diabetic ketoacidosis.
    • Type II diabetes mellitus is basically where the body cannot effectively utilise sugars to produce energy due to the fact that its cells have become unresponsive to the hormone, insulin, which allows cells to utilise sugars for energy.
    • This in turn forces the body to burn fats for energy and fats require conversion to ketone bodies in order to be utilised by the cells of the body as an energy source.
    • The ketone bodies are acidic hence when the body is entirely reliant on these ketone bodies for energy the levels in the blood reaches a point where it overwhelms the body’s natural mechanisms to keep blood pH (a measure of acidity) within a safe range, leading to the blood becoming acidic which is potentially damaging to the tissues of the body due to the ability of acidic environments to denature the proteins of the body.
  • Anaphylactic reaction a potentially life-threatening allergic reaction.
  • Sudden cardiac death.

What is Neuroleptic Malignant Syndrome?

Introduction

Neuroleptic malignant syndrome (NMS) is a rare but life-threatening reaction that can occur in response to neuroleptic or antipsychotic medication. Symptoms include high fever, confusion, rigid muscles, variable blood pressure, sweating, and fast heart rate. Complications may include rhabdomyolysis, high blood potassium, kidney failure, or seizures.

Any medications within the family of neuroleptics can cause the condition, though typical antipsychotics appear to have a higher risk than atypicals, specifically first generation antipsychotics like haloperidol. Onset is often within a few weeks of starting the medication but can occur at any time. Risk factors include dehydration, agitation, and catatonia.

Rapidly decreasing the use of levodopa or other dopamine agonists, such as pramipexole, may also trigger the condition. The underlying mechanism involves blockage of dopamine receptors. Diagnosis is based on symptoms.

Management includes stopping the offending medication, rapid cooling, and starting other medications. Medications used include dantrolene, bromocriptine, and diazepam. The risk of death among those affected is about 10%. Rapid diagnosis and treatment is required to improve outcomes. Many people can eventually be restarted on a lower dose of antipsychotic.

As of 2011, among those in psychiatric hospitals on neuroleptics about 15 per 100,000 are affected per year (0.015%). In the second half of the 20th century rates were over 100 times higher at about 2% (2,000 per 100,000). Males appear to be more often affected than females. The condition was first described in 1956.

Brief History

NMS was known about as early as 1956, shortly after the introduction of the first phenothiazines. NMS was first described in 1960 by French clinicians who had been working on a study involving haloperidol. They characterized the condition that was associated with the side effects of haloperidol “syndrome malin des neuroleptiques”, which was translated to neuroleptic malignant syndrome.

Signs and Symptoms

The first symptoms of neuroleptic malignant syndrome are usually muscle cramps and tremors, fever, symptoms of autonomic nervous system instability such as unstable blood pressure, and sudden changes in mental status (agitation, delirium, or coma). Once symptoms appear, they may progress rapidly and reach peak intensity in as little as three days. These symptoms can last anywhere from eight hours to forty days.

Symptoms are sometimes misinterpreted by doctors as symptoms of mental illness which can result in delayed treatment. NMS is less likely if a person has previously been stable for a period of time on antipsychotics, especially in situations where the dose has not been changed and there are no issues of noncompliance or consumption of psychoactive substances known to worsen psychosis.

  • Increased body temperature >38 °C (>100.4 °F);
  • Confused or altered consciousness;
  • sweating;
  • Rigid muscles; and/or
  • Autonomic imbalance.

Causes

NMS is usually caused by antipsychotic drug use, and a wide range of drugs can result in NMS. Individuals using butyrophenones (such as haloperidol and droperidol) or phenothiazines (such as promethazine and chlorpromazine) are reported to be at greatest risk. However, various atypical antipsychotics such as clozapine, olanzapine, risperidone, quetiapine, and ziprasidone have also been implicated in cases.

NMS may also occur in people taking dopaminergic drugs (such as levodopa) for Parkinson’s disease, most often when the drug dosage is abruptly reduced. In addition, other drugs with anti-dopaminergic activity, such as the antiemetic metoclopramide, can induce NMS. Tetracyclics with anti-dopaminergic activity have been linked to NMS in case reports, such as the amoxapines. Additionally, desipramine, dothiepin, phenelzine, tetrabenazine, and reserpine have been known to trigger NMS. Whether lithium can cause NMS is unclear.

At the molecular level, NMS is caused by a sudden, marked reduction in dopamine activity, either from withdrawal of dopaminergic agents or from blockade of dopamine receptors.

Risk Factors

One of the clearest risk factors in the development of NMS is the course of drug therapy chosen to treat a condition. Use of high-potency neuroleptics, a rapid increase in the dosage of neuroleptics, and use of long-acting forms of neuroleptics are all known to increase the risk of developing NMS.

It has been purported that there is a genetic risk factor for NMS, since identical twins have both presented with NMS in one case, and a mother and two of her daughters have presented with NMS in another case.

Demographically, it appears that males, especially those under forty, are at greatest risk for developing NMS, although it is unclear if the increased incidence is a result of greater neuroleptic use in men under forty. It has also been suggested that postpartum women may be at a greater risk for NMS.

An important risk factor for this condition is Lewy body dementia. These patients are extremely sensitive to neuroleptics. As a result, neuroleptics should be used cautiously in all cases of dementia.

Pathophysiology

The mechanism is commonly thought to depend on decreased levels of dopamine activity due to:

  • Dopamine receptor blockade.
  • Genetically reduced function of dopamine receptor D2.

It has been proposed that blockade of D2-like (D2, D3 and D4) receptors induce massive glutamate release, generating catatonia, neurotoxicity and myotoxicity. Additionally, the blockade of diverse serotonin receptors by atypical antipsychotics and activation of 5HT1 receptors by certain of them reduces GABA release and indirectly induces glutamate release, worsening this syndrome.

The muscular symptoms are most likely caused by blockade of the dopamine receptor D2, leading to abnormal function of the basal ganglia similar to that seen in Parkinson’s disease.

However, the failure of D2 dopamine receptor antagonism, or dopamine receptor dysfunction, do not fully explain the presenting symptoms and signs of NMS, as well as the occurrence of NMS with atypical antipsychotic drugs with lower D2 dopamine activity. This has led to the hypothesis of sympathoadrenal hyperactivity (results from removing tonic inhibition from the sympathetic nervous system) as a mechanism for NMS. Release of calcium is increased from the sarcoplasmic reticulum with antipsychotic usage. This can result in increased muscle contractility, which can play a role in the breakdown of muscle, muscle rigidity, and hyperthermia. Some antipsychotic drugs, such as typical neuroleptics, are known to block dopamine receptors; other studies have shown that when drugs supplying dopamine are withdrawn, symptoms similar to NMS present themselves.

There is also thought to be considerable overlap between malignant catatonia and NMS in their pathophysiology, the former being idiopathic and the latter being the drug-induced form of the same syndrome.

The raised white blood cell count and creatine phosphokinase (CPK) plasma concentration seen in those with NMS is due to increased muscular activity and rhabdomyolysis (destruction of muscle tissue). The patient may suffer hypertensive crisis and metabolic acidosis. A non-generalized slowing on an EEG is reported in around 50% of cases.

The fever seen with NMS is believed to be caused by hypothalamic dopamine receptor blockade. The peripheral problems (the high white blood cell and CPK count) are caused by the antipsychotic drugs. They cause an increased calcium release from the sarcoplasmic reticulum of muscle cells which can result in rigidity and eventual cell breakdown. No major studies have reported an explanation for the abnormal EEG, but it is likely also attributable to dopamine blockage leading to changes in neuronal pathways.

Diagnosis

Differential Diagnosis

Differentiating NMS from other neurological disorders can be very difficult. It requires expert judgement to separate symptoms of NMS from other diseases. Some of the most commonly mistaken diseases are encephalitis, toxic encephalopathy, status epilepticus, heat stroke, catatonia and malignant hyperthermia. Due to the comparative rarity of NMS, it is often overlooked and immediate treatment for the syndrome is delayed. Drugs such as cocaine and amphetamine may also produce similar symptoms.

The differential diagnosis is similar to that of hyperthermia, and includes serotonin syndrome. Features which distinguish NMS from serotonin syndrome include bradykinesia, muscle rigidity, and a high white blood cell count.

Treatment

NMS is a medical emergency and can lead to death if untreated. The first step is to stop the antipsychotic medication and treat the hyperthermia aggressively, such as with cooling blankets or ice packs to the axillae and groin. Supportive care in an intensive care unit capable of circulatory and ventilatory support is crucial. The best pharmacological treatment is still unclear. Dantrolene has been used when needed to reduce muscle rigidity, and more recently dopamine pathway medications such as bromocriptine have shown benefit. Amantadine is another treatment option due to its dopaminergic and anticholinergic effects. Apomorphine may be used however its use is supported by little evidence. Benzodiazepines may be used to control agitation. Highly elevated blood myoglobin levels can result in kidney damage, therefore aggressive intravenous hydration with diuresis may be required. When recognised early NMS can be successfully managed; however, up to 10% of cases can be fatal.

Should the affected person subsequently require an antipsychotic, trialling a low dose of a low-potency atypical antipsychotic is recommended.

Prognosis

The prognosis is best when identified early and treated aggressively. In these cases NMS is not usually fatal. In earlier studies the mortality rates from NMS ranged from 20%-38%, but by 2009 mortality rates were reported to have fallen below 10% over the previous two decades due to early recognition and improved management. Re-introduction to the drug that originally caused NMS to develop may also trigger a recurrence, although in most cases it does not.

Memory impairment is a consistent feature of recovery from NMS, and is usually temporary though in some cases may become persistent.

Epidemiology

Pooled data suggest the incidence of NMS is between 0.2%-3.23%. However, greater physician awareness coupled with increased use of atypical anti-psychotics have likely reduced the prevalence of NMS. Additionally, young males are particularly susceptible and the male-female ratio has been reported to be as high as 2:1.

Research

While the pathophysiology of NMS remains unclear, the two most prevalent theories are:

  • Reduced dopamine activity due to receptor blockade.
  • Sympathoadrenal hyperactivity and autonomic dysfunction.

In the past, research and clinical studies seemed to corroborate the D2 receptor blockade theory in which antipsychotic drugs were thought to significantly reduce dopamine activity by blocking the D2 receptors associated with this neurotransmitter. However, recent studies indicate a genetic component to the condition. In support of the sympathoadrenal hyperactivity model proposed, it has been hypothesized that a defect in calcium regulatory proteins within the sympathetic neurons may bring about the onset of NMS. This model of NMS strengthens its suspected association with malignant hyperthermia in which NMS may be regarded as a neurogenic form of this condition which itself is linked to defective calcium-related proteins.

The introduction of atypical antipsychotic drugs, with lower affinity to the D2 dopamine receptors, was thought to have reduced the incidence of NMS. However, recent studies suggest that the decrease in mortality may be the result of increased physician awareness and earlier initiation of treatment rather than the action of the drugs themselves. NMS induced by atypical drugs also resembles “classical” NMS (induced by “typical” antipsychotic drugs), further casting doubt on the overall superiority of these drugs.

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 Trimipramine?

Introduction

Trimipramine, sold under the brand name Surmontil among others, is a tricyclic antidepressant (TCA) which is used to treat depression.

It has also been used for its sedative, anxiolytic, and weak antipsychotic effects in the treatment of insomnia, anxiety disorders, and psychosis, respectively. The drug is described as an atypical or “second-generation” TCA because, unlike other TCAs, it seems to be a fairly weak monoamine reuptake inhibitor. Similarly to other TCAs however, trimipramine does have antihistamine, antiserotonergic, antiadrenergic, antidopaminergic, and anticholinergic activities.

Brief History

Trimipramine was developed by Rhône-Poulenc. It was patented in 1959 and first appeared in the literature in 1961. The drug was first introduced for medical use in 1966, in Europe. It was not introduced in the United States until later in 1979 or 1980.

Medical Uses

Trimipramine’s primary use in medicine is in the treatment of major depressive disorder, especially where sedation is helpful due to its prominent sedative effects. The drug is also an effective anxiolytic, and can be used in the treatment of anxiety. In addition to depression and anxiety, trimipramine is effective in the treatment of insomnia, and unlike most other hypnotics, does not alter the normal sleep architecture. In particular, it does not suppress REM sleep, and dreams are said to “brighten” during treatment. Trimipramine also has some weak antipsychotic effects with a profile of activity described as similar to that of clozapine, and may be useful in the treatment of psychotic symptoms such as in delusional depression or schizophrenia.

Contraindications

Contraindications include:

  • Recent myocardial infarction.
  • Any degree of heart block or other cardiac arrhythmias.
  • Mania.
  • Severe liver disease.
  • During breastfeeding.
  • Hypersensitivity to trimipramine or to any of the excipients.

Side Effects

The side effects of trimipramine have been said to be similar to those of other tertiary amine TCAs, with a preponderance of anticholinergic and sedative effects. However, trimipramine has also been said to be associated with a different side effect profile compared to other TCAs and in general with fewer side effects, chiefly due to its lack of norepinephrine reuptake inhibition and relatively lower anticholinergic effects (although it is still a potent anticholinergic). Somnolence is the most common side effect of the drug. Dry mouth is the most common anticholinergic side effect, but others like constipation, urinary retention, and blurred vision are also present.

It is described as being associated with minimal or no orthostatic hypotension, at least in comparison to clomipramine, in spite of its potent and comparable activity as an alpha-1 blocker. However, it has also been said to have a rate of orthostatic hypotension similar to that of other TCAs. Trimipramine is said to be less epileptogenic than other TCAs, although seizures have still been reported in association with it. It is also less cardiotoxic than other TCAs and cardiotoxicity is said to be minimal, with a “very favourable profile”.

List of Side Effects

Common adverse effects include:

  • Sedation:
    • Especially common with trimipramine compared to the other TCAs.
  • Anticholinergic effects including:
    • Dry mouth.
    • Blurred vision.
    • Mydriasis.
    • Decreased lacrimation.
    • Constipation.
    • Urinary hesitancy or retention.
    • Reduced GI motility.
    • Tachycardia (high heart rate).
    • Anticholinergic delirium (particularly in the elderly and in Parkinson’s disease).
  • Weight gain.
  • Orthostatic hypotension.
  • Sexual dysfunction including impotence, loss of libido and other sexual adverse effects.
  • Tremor.
  • Dizziness.
  • Sweating.
  • Anxiety.
  • Insomnia.
  • Agitation.
  • Rash.

Adverse effects with an unknown incidence includes:

  • Confusion.
  • Nausea.
  • Vomiting.
  • Extrapyramidal side effects (e.g. parkinsonism, dystonia, etc.).
  • Tinnitus.
  • Paraesthesia.
  • ECG changes.
  • Increased liver function tests.

Rare adverse effects include:

  • Seizures.
  • Syndrome of inappropriate secretion of antidiuretic hormone.
  • Blood dyscrasias including:
    • Agranulocytosis.
    • Thrombocytopenia.
    • Eosinophilia.
    • Leukopenia.
  • Myocardial infarction.
  • Heart block.
  • QTc interval prolongation.
  • Sudden cardiac death.
  • Depression worsening.
  • Suicidal ideation.

Overdose

Refer to Tricyclic Antidepressant Overdose.

Compared to other TCAs, trimipramine is relatively safe in overdose, although it is more dangerous than the selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) but less dangerous than bupropion in cases of overdose.

Interactions

Trimipramine should not be given with sympathomimetic agents such as epinephrine (adrenaline), ephedrine, isoprenaline, norepinephrine (noradrenaline), phenylephrine and phenylpropanolamine.

Barbiturates may increase the rate of metabolism. Trimipramine should be administered with care in patients receiving therapy for hyperthyrodism.

Genotoxicity

Heavy exposure to any tricyclic antidepressants was associated with an elevated rate ratio for breast cancer 11–15 years later. However, on tests done on Drosophila melanogaster, nongenotoxic TCAs (amitriptyline, maprotiline, nortriptyline, and protriptyline), and genotoxic TCAs (amoxapine, clomipramine, desipramine, doxepin, imipramine, and trimipramine) were identified.

Pharmacology

Pharmacodynamics

The mechanism of action of trimipramine in terms of its antidepressant effects differs from that of other TCAs and is not fully clear. The mechanism of action of its anxiolytic effects is similarly unclear. Trimipramine is a very weak reuptake inhibitor of serotonin, norepinephrine, and dopamine (see below), and unlike most other TCAs, has been claimed to be devoid of clinically significant monoamine reuptake inhibition. The effects of the drug are thought to be mainly due to receptor antagonism as follows:

  • Very strong: H1.
  • Strong: 5-HT2A, α1-adrenergic.
  • Moderate: D2, mACh.
  • Weak: 5-HT2C, D1, α2-adrenergic.

In spite of its atypical nature and different profile of activity, trimipramine has been shown in head-to-head clinical studies to possess equivalent effectiveness to other antidepressants, including but not limited to other TCAs (e.g. amitriptyline, imipramine, doxepin, amineptine), tetracyclic antidepressants (TeCAs) (e.g. maprotiline), monoamine oxidase inhibitors (MAOIs) (e.g. phenelzine, isocarboxazid), and selective serotonin reuptake inhibitors (e.g. fluoxetine). In addition, trimipramine has been found to possess greater anxiolytic effects than other TCAs such as amitriptyline and doxepin in head-to-head comparisons. Indeed, its prominent anxiolytic effects have been said to distinguish it from most other TCAs. The atypicality of trimipramine in relation to its lack of monoamine reuptake inhibition is described as challenging the monoamine hypothesis of depression.

The major metabolite of trimipramine, desmethyltrimipramine, is considered to possess pharmacological activity similar to that of other demethylated tertiary amine TCA variants.

Monoamine Reuptake Inhibition

Studies have generally found only very weak inhibition of serotonin and norepinephrine reuptake with trimipramine, and the drug has been described by various authors as devoid of monoamine reuptake inhibition. Richelson & Pfenning (1984) found a relatively high Ki for the NET of 510 nM in rat brain synaptosomes and Tatsumi et al. (1997) found a relatively high KD of 149 nM for the SERT in human HEK293 cells, but other authors and a more recent study with an improved design have not had the same findings. In the most recent study, by Haenisch et al. (2011), the researchers suggested that the discrepant findings from the Tatsumi et al. study were due to methodological differences, in particular the use of radioligand binding in isolated membranes (KD) to study interactions as opposed to actual functional reuptake inhibition (IC50).

Trimipramine is extensively metabolized, so its metabolites may contribute to its pharmacology, including potentially to monoamine reuptake inhibition. In what was the only study to date to have assessed the activity profiles of the metabolites of trimipramine, Haenisch et al. (2011) assayed desmethyltrimipramine, 2-hydroxytrimipramine, and trimipramine-N-oxide in addition to trimipramine and found that these metabolites showed IC50 values for the SERT, NET, and DAT similar to those of trimipramine (see table to the right). Like other secondary amine TCAs, desmethyltrimipramine was slightly more potent than trimipramine in its norepinephrine reuptake inhibition but less potent in its inhibition of serotonin reuptake. However, desmethyltrimipramine still showed only very weak inhibition of the NET.

Therapeutic concentrations of trimipramine are between 0.5 and 1.2 μM (150-350 ng/mL) and hence significant monoamine reuptake inhibition would not be expected with it or its metabolites. However, these concentrations are nearly 2-fold higher if the active metabolites of trimipramine are also considered, and studies of other TCAs have found that they cross the blood-brain barrier and accumulate in the brain to levels of up to 10-fold those in the periphery. As such, trimipramine and its metabolites might at least partially inhibit reuptake of serotonin and/or norepinephrine, though not of dopamine, at therapeutic concentrations, and this could be hypothesized to contribute at least in part to its antidepressant effects. This is relevant as Haenisch et al. has stated that these are the only actions known at present which could explain or at least contribute to the antidepressant effects of trimipramine. That said, blockade of the 5-HT2A, 5-HT2C, and α2-adrenergic receptors, as with mirtazapine, has also been implicated in antidepressant effects.

In any case, there is also clinical and animal evidence that trimipramine does not inhibit the reuptake of monoamines. Unlike other TCAs, it does not downregulate β3-adrenergic receptors, which is likely the reason that it does not cause orthostatic hypotension. It can be safely combined with MAOIs apparently without risk of serotonin syndrome or hypertensive crisis. Indeed, in rabbits, whereas hyperpyrexia (a symptom of serotonin syndrome) occurs with imipramine and an MAOI and to a lesser extent with amitriptyline and an MAOI, it does not occur at all with trimipramine and an MAOI, likely due to trimipramine’s lack of serotonin reuptake inhibition.

Antihistamine Activity

Trimipramine is a very potent antihistamine; it has the third highest affinity for the H1 receptor (Ki = 0.27 nM) after mirtazapine (Ki = 0.14 nM) and doxepin (Ki = 0.24 nM) among the TCAs and tetracyclic antidepressants (TeCAs). The TeCA mianserin (Ki = 0.40) and the TCA amitriptyline (Ki = 1.0) are also very potent H1 receptor antagonists, whereas other TCAs and TeCAs are less potent. These TCAs and TeCAs, including trimipramine, are far more potent than the standard antihistamine diphenhydramine (approximately 800 times for doxepin and 250 times for trimipramine), and are among the most potent antihistamines available.

Trimipramine is also an antagonist of the H2 receptor with lower potency and has been found to be effective in the treatment of duodenal ulcers.

As a Hypnotic

Blockade of the H1 receptor is responsible for the sedative effects of trimipramine and other TCAs and their effectiveness in the treatment of insomnia.

Most antidepressants suppress REM sleep, in parallel with their alleviation of depressive symptoms (although suppression of REM sleep is not required for antidepressant effects). This includes TCAs (e.g. amitriptyline, nortriptyline), TeCAs (e.g. mianserin, maprotiline), MAOIs (e.g. clorgiline, pargyline), and SSRIs (e.g. fluoxetine, zimelidine, indalpine). Trimipramine is unique in that it is an exception and produces antidepressant effects without compromising or otherwise affecting REM sleep. Even long-term treatment with trimipramine for up to 2 years has not been found to suppress REM sleep. In addition, trimipramine has been found to decrease nocturnal cortisol levels to normal and to normalize cortisol response in depressed patients; hence, it normalizes the hypothalamic-pituitary-adrenal axis, whereas imipramine and other antidepressants tend to increase nocturnal cortisol secretion.

In clinical studies, trimipramine has been found in doses of 50 to 200 mg/day to significantly increase sleep efficiency and total sleep time and to decrease waking time for up to 3 weeks in patients with insomnia. It also improved subjectively perceived sleep quality and well-being during daytime. Monitoring of patients upon discontinuation of trimipramine found that it did not cause rebound insomnia or worsening of sleep quality in subjective evaluations of sleep, although objective measurements found total sleep time below baseline in a subset of patients during trimipramine withdrawal.

Antidopaminergic Activity

Trimipramine is a weak but significant antagonist of the dopamine D1 and D2 receptors, and also binds to the D4 receptor (Ki = 275 nM). Its affinities for various monoamine receptors including the D2 and 5-HT2A receptors closely resemble those of the atypical antipsychotic clozapine. In accordance, high doses of trimipramine have been found to have antipsychotic effects in schizophrenic patients, notably without causing extrapyramidal symptoms, and trimipramine has recently been found to be effective in reducing psychotic symptoms in patients with delusional depression. The lack of extrapyramidal symptoms with trimipramine may be related to its affinity for the D4 receptor, these both being properties it shares with clozapine. Unlike other TCAs, but reminiscent of antipsychotics, trimipramine has been found to markedly increase plasma prolactin levels (a marker of D2 receptor antagonism) at a dose of 75 mg/day and to increase nocturnal prolactin secretion at doses of 75 and 200 mg/day. These findings are suggestive of important antidopaminergic actions of trimipramine.

Unlike various other TCAs, trimipramine shows marked antagonism of presynaptic dopamine autoreceptors, potentially resulting in increased dopaminergic neurotransmission. This effect has also been observed with low-potency tricyclic antipsychotics like thioridazine and chlorprothixene. Notably, these two antipsychotics have been claimed many times to also possess antidepressant effects. As such, blockade of inhibitory dopamine autoreceptors and hence facilitation of dopaminergic signalling could be involved in the antidepressant effects of trimipramine. However, other authors have attributed the claimed antidepressant effects of antipsychotics like the two previously mentioned to α2-adrenergic receptor antagonism, although trimipramine specifically has only weak affinity for this receptor. Aside from antidepressant effects, low doses of antipsychotics have been found to increase REM sleep, and so dopamine autoreceptor antagonism could be involved in the unique effects of trimipramine in terms of REM sleep and sleep architecture.

Pharmacokinetics

The time to peak concentrations following a dose is 2 to 4 hours. The typical antidepressant therapeutic range of trimipramine concentrations is 150 to 300 ng/mL. The terminal half-life of trimipramine has been variously reported to be as little as 8 hours (in plasma) and as long as 24 hours. In any case, the terminal half-life of trimipramine is described as shorter than that of other TCAs, which makes it ideal for use in the treatment of insomnia.

Trimipramine is a racemic compound with two enantiomers. CYP2C19 is responsible for the demethylation of (D)- and (L)-trimipramine to (D)- (L)-desmethyltrimipramine, respectively, and CYP2D6 is responsible for the 2-hydroxylation of (D)- and (L)-desmethyltrimipramine to (D)- and (L)-2-hydroxydesmethyltrimipramine, respectively. CYP2D6 also metabolises (L)-trimipramine into (L)-2-hydroxytrimipramine.

Chemistry

Trimipramine is a tricyclic compound, specifically a dibenzazepine, and possesses three rings fused together with a side chain attached in its chemical structure. Other dibenzazepine TCAs include imipramine, desipramine, and clomipramine. Trimipramine is a derivative of imipramine with a methyl group added to its side chain and is also known as 2′-methylimipramine or β-methylimipramine. The tri- prefix in its name may allude to the fact that its side chain features three methyl groups. Trimipramine is a tertiary amine TCA, with its side chain-demethylated metabolite desmethyltrimipramine being a secondary amine. Other tertiary amine TCAs include amitriptyline, imipramine, clomipramine, dosulepin (dothiepin), and doxepin. The chemical name of trimipramine is 3-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-N,N,2-trimethylpropan-1-amine and its free base form has a chemical formula of C20H26N2 with a molecular weight of 294.434 g/mol. The drug is used commercially as the maleate salt. The CAS Registry Number of the free base is 739-71-9 and of the maleate is 521-78-8.

Society and Culture

Generic Names

Trimipramine is the generic name of the drug and its INN, USAN, BAN, and DCF, while trimipramine maleate is its USAN, USP, BANM, and JAN. Its generic name in Latin is trimipraminum, in German is trimipramin, and in Spanish is trimipramina.

Brand Names

Trimipramine is marketed throughout the world mainly under the brand name Surmontil. Other notable brand names of trimipramine have included Herphonal, Rhotrimine, Sapilent, Stangyl, and Tydamine.

Availability

Trimipramine is no longer marketed in Australia, though it was previously.

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 an Antipsychotic?

Introduction

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

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

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

The use of antipsychotics may result in many unwanted side effects such as involuntary movement disorders, gynecomastia, impotence, weight gain and metabolic syndrome. Long-term use can produce adverse effects such as tardive dyskinesia.

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

Brief History

The original antipsychotic drugs were happened upon largely by chance and then tested for their effectiveness. The first, chlorpromazine, was developed as a surgical anaesthetic. It was first used on psychiatric patients because of its powerful calming effect; at the time it was regarded as a non-permanent “pharmacological lobotomy”. Lobotomy at the time was used to treat many behavioural disorders, including psychosis, although its effect was to markedly reduce behaviour and mental functioning of all types. However, chlorpromazine proved to reduce the effects of psychosis in a more effective and specific manner than lobotomy, even though it was known to be capable of causing severe sedation. The underlying neurochemistry involved has since been studied in detail, and subsequent antipsychotic drugs have been discovered by an approach that incorporates this sort of information.

The discovery of chlorpromazine’s psychoactive effects in 1952 led to further research that resulted in the development of antidepressants, anxiolytics, and the majority of other drugs now used in the management of psychiatric conditions. In 1952, Henri Laborit described chlorpromazine only as inducing indifference towards what was happening around them in nonpsychotic, non-manic patients, and Jean Delay and Pierre Deniker described it as controlling manic or psychotic agitation. The former claimed to have discovered a treatment for agitation in anyone, and the latter team claimed to have discovered a treatment for psychotic illness.

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

Antipsychotics are broadly divided into two groups, the typical or first-generation antipsychotics and the atypical or second-generation antipsychotics. The difference between first- and second-generation antipsychotics is a subject of debate. The second-generation antipsychotics are generally distinguishable by the presence of 5HT2A receptor antagonism and a corresponding lower propensity for extrapyramidal side effects compared to first-generation antipsychotics.

Medical Uses

Antipsychotics are most frequently used for the following conditions:

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

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

Schizophrenia

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

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

Prevention of Psychosis and Symptom Improvement

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

First Episode Psychosis

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

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

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

Recurrent Psychotic Episodes

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

Maintenance Therapy

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

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

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

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

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

Bipolar Disorder

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

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

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

Dementia

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

Major Depressive Disorder

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

Other

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

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

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

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

Typicals vs Atypicals

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

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

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

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

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

Many researchers question the first-line prescribing of atypicals over typicals, and some even question the distinction between the two classes. In contrast, other researchers point to the significantly higher risk of tardive dyskinesia and other extrapyramidal symptoms with the typicals and for this reason alone recommend first-line treatment with the atypicals, notwithstanding a greater propensity for metabolic adverse effects in the latter. NICE recently revised its recommendation favouring atypicals, to advise that the choice should be an individual one based on the particular profiles of the individual drug and on the patient’s preferences.

The re-evaluation of the evidence has not necessarily slowed the bias toward prescribing the atypical

Adverse Effects

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

Very rarely antipsychotics may cause tardive psychosis.

By Rate

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

  • Sedation (particularly common with asenapine, clozapine, olanzapine, quetiapine, chlorpromazine and zotepine).
  • Headaches.
  • Dizziness.
  • Diarrhoea.
  • Anxiety.
  • Extrapyramidal side effects (particularly common with first-generation antipsychotics), which include:
    • Akathisia, an often distressing sense of inner restlessness.
    • Dystonia, an abnormal muscle contraction.
    • Pseudoparkinsonism, symptoms that are similar to what people with Parkinson’s disease experience, including tremulousness and drooling.
  • Hyperprolactinaemia (rare for those treated with clozapine, quetiapine and aripiprazole), which can cause:
    • Galactorrhoea, the unusual secretion of breast milk.
    • Gynaecomastia, abnormal growth of breast tissue.
    • Sexual dysfunction (in both sexes).
    • Osteoporosis.
  • Orthostatic hypotension.
  • Weight gain (particularly prominent with clozapine, olanzapine, quetiapine and zotepine).
  • Anticholinergic side-effects (common for olanzapine, clozapine; less likely on risperidone) such as:
    • Blurred vision.
    • Constipation.
    • Dry mouth (although hypersalivation may also occur).
    • Reduced perspiration.
  • Tardive dyskinesia appears to be more frequent with high-potency first-generation antipsychotics, such as haloperidol, and tends to appear after chronic and not acute treatment. It is characterised by slow (hence the tardive) repetitive, involuntary and purposeless movements, most often of the face, lips, legs, or torso, which tend to resist treatment and are frequently irreversible. The rate of appearance of TD is about 5% per year of use of antipsychotic drug (whatever the drug used).

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

  • Blood dyscrasias (e.g., agranulocytosis, leukopenia, and neutropoenia), which is more common in patients on clozapine.
  • Metabolic syndrome and other metabolic problems such as type II diabetes mellitus – particularly common with clozapine, olanzapine and zotepine. In American studies African Americans appeared to be at a heightened risk for developing type II diabetes mellitus. Evidence suggests that females are more sensitive to the metabolic side effects of first-generation antipsychotic drugs than males. Metabolic adverse effects appear to be mediated by the following mechanisms:
    • Causing weight gain by antagonising the histamine H1 and serotonin 5-HT2Creceptors] and perhaps by interacting with other neurochemical pathways in the central nervous system.
  • Neuroleptic malignant syndrome, a potentially fatal condition characterised by:
    • Autonomic instability, which can manifest with tachycardia, nausea, vomiting, diaphoresis, etc.
    • Hyperthermia – elevated body temperature.
    • Mental status change (confusion, hallucinations, coma, etc.).
    • Muscle rigidity.
    • Laboratory abnormalities (e.g. elevated creatine kinase, reduced iron plasma levels, electrolyte abnormalities, etc.).
  • Pancreatitis.
  • QT interval prolongation – more prominent in those treated with amisulpride, pimozide, sertindole, thioridazine and ziprasidone.
  • Torsades de pointes.
  • Seizures, particularly in people treated with chlorpromazine and clozapine.
  • Thromboembolism.
  • Myocardial infarction.
  • Stroke.

Long-Term Effects

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

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

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

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

Discontinuation

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

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

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

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

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

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

List of Agents

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

Notes:

  • † indicates drugs that are no longer (or were never) marketed in English-speaking countries.
  • ‡ denotes drugs that are no longer (or were never to begin with) marketed in the United States. Some antipsychotics are not firmly placed in either first-generation or second-generation classes.
  • # denotes drugs that have been withdrawn worldwide.

First-Generation (Typical)

  • Butyrophenones:
    • Benperidol‡
    • Bromperidol†
    • Droperidol‡
    • Haloperidol
    • Moperone (discontinued)†
    • Pipamperone (discontinued)†
    • Timiperone †
  • Diphenylbutylpiperidines:
    • Fluspirilene ‡
    • Penfluridol ‡
    • Pimozide
  • Phenothiazines:
    • Acepromazine † – although it is mostly used in veterinary medicine.
    • Chlorpromazine
    • Cyamemazine †
    • Dixyrazine †
    • Fluphenazine
    • Levomepromazine‡
    • Mesoridazine (discontinued)†
    • Perazine
    • Pericyazine‡
    • Perphenazine
    • Pipotiazine ‡
    • Prochlorperazine
    • Promazine (discontinued)
    • Promethazine
    • Prothipendyl †
    • Thioproperazine‡ (only English-speaking country it is available in is Canada)
    • Thioridazine (discontinued)
    • Trifluoperazine
    • Triflupromazine (discontinued)†
  • Thioxanthenes:
    • Chlorprothixene †
    • Clopenthixol
    • Flupentixol ‡
    • Thiothixene
    • Zuclopenthixol ‡

Disputed/Unknown

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

  • Benzamides:
    • Sulpiride ‡
    • Sultopride †
    • Veralipride †
  • Tricyclics:
    • Carpipramine †
    • Clocapramine †
    • Clorotepine †
    • Clotiapine ‡
    • Loxapine
    • Mosapramine †
  • Others:
    • Molindone #

Second-Generation (Atypical)

  • Benzamides:
    • Amisulpride ‡ – Selective dopamine antagonist. Higher doses (greater than 400 mg) act upon post-synaptic dopamine receptors resulting in a reduction in the positive symptoms of schizophrenia, such as psychosis. Lower doses, however, act upon dopamine autoreceptors, resulting in increased dopamine transmission, improving the negative symptoms of schizophrenia. Lower doses of amisulpride have also been shown to have antidepressant and anxiolytic effects in non-schizophrenic patients, leading to its use in dysthymia and social phobias.
    • Nemonapride † – Used in Japan.
    • Remoxipride # – Has a risk of causing aplastic anaemia and, hence, has been withdrawn from the market worldwide. It has also been found to possess relatively low (virtually absent) potential to induce hyperprolactinaemia and extrapyramidal symptoms, likely attributable to its comparatively weak binding to (and, hence, rapid dissociation from) the D2 receptor.
    • Sultopride – An atypical antipsychotic of the benzamide chemical class used in Europe, Japan, and Hong Kong for the treatment of schizophrenia. It was launched by Sanofi-Aventis in 1976. Sultopride acts as a selective D2 and D3 receptor antagonist.
  • Benzisoxazoles/benzisothiazoles:
    • Iloperidone – Approved by the FDA in 2009, it is fairly well tolerated, although hypotension, dizziness, and somnolence were very common side effects. Has not received regulatory approval in other countries, however.
    • Lurasidone – Approved by the FDA for schizophrenia and bipolar depression, and for use as schizophrenia treatment in Canada.
    • Paliperidone – Primary, active metabolite of risperidone that was approved in 2006.
    • Paliperidone palmitate – Long-acting version of paliperidone for once-monthly injection.
    • Perospirone † – Has a higher incidence of extrapyramidal side effects than other atypical antipsychotics.
    • Risperidone – Divided dosing is recommended until initial titration is completed, at which time the drug can be administered once daily. Used off-label to treat Tourette syndrome and anxiety disorder.
    • Ziprasidone – Approved in 2004 to treat bipolar disorder. Side-effects include a prolonged QT interval in the heart, which can be dangerous for patients with heart disease or those taking other drugs that prolong the QT interval.
  • Butyrophenones:
    • Melperone † – Only used in a few European countries. No English-speaking country has licensed it to date.
    • Lumateperone.
  • Phenylpiperazines/quinolinones:
    • Aripiprazole – Partial agonist at the D2 receptor unlike almost all other clinically-utilized antipsychotics.
    • Aripiprazole lauroxil – Long-acting version of aripiprazole for injection.
    • Brexpiprazole – Partial agonist of the D2 receptor. Successor of aripiprazole.
    • Cariprazine – A D3-preferring D2/D3 partial agonist.
  • Tricyclics:
    • Asenapine – Used for the treatment of schizophrenia and acute mania associated with bipolar disorder.
    • Clozapine – Requires routine laboratory monitoring of complete blood counts every one to four weeks due to the risk of agranulocytosis. It has unparalleled efficacy in the treatment of treatment-resistant schizophrenia.
    • Olanzapine – Used to treat psychotic disorders including schizophrenia, acute manic episodes, and maintenance of bipolar disorder. Used as an adjunct to antidepressant therapy, either alone or in combination with fluoxetine as Symbyax.
    • Quetiapine – Used primarily to treat bipolar disorder and schizophrenia. Also used and licensed in a few countries (including Australia, the United Kingdom and the United States) as an adjunct to antidepressant therapy in patients with major depressive disorder. It is the only antipsychotic that has demonstrated efficacy as a monotherapy for the treatment of major depressive disorder. It indirectly serves as a norepinephrine reuptake inhibitor by means of its active metabolite, norquetiapine.
    • Zotepine – An atypical antipsychotic indicated for acute and chronic schizophrenia. It is still used in Japan and was once used in Germany but it was discontinued.†
  • Others:
    • Blonanserin – Approved by the PMDA in 2008. Used in Japan and South Korea.
    • Pimavanserin – A selective 5-HT2A receptor antagonist approved for the treatment of Parkinson’s disease psychosis in 2016.
    • Sertindole ‡ – Developed by the Danish pharmaceutical company H. Lundbeck. Like the other atypical antipsychotics, it is believed to have antagonist activity at dopamine and serotonin receptors in the brain.

Mechanism of Action

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

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

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

Society and Culture

Terminology

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

Antipsychotics are a type of psychoactive or psychotropic medication.

Sales

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

Overprescription

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

Legal

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

Formulations

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

Recreational Use

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

Controversy

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

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

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

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

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

Special Populations

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