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What is Neuroleptic Malignant Syndrome?

Published on by Andrew Marshall2 Comments

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 Haloperidol?

Published on by Andrew Marshall30 Comments

Introduction

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

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

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

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

Refer to Haloperidol Decanoate.

Brief History

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

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

Medical Uses

Haloperidol is used in the control of the symptoms of:

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

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

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

Pregnancy and Lactation

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

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

Other Considerations

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

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

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

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

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

Adverse Effects

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

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

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

Contraindications

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

Special Cautions

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

Interactions

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

Discontinuation

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

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

Overdose

Symptoms

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

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

Treatment

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

Prognosis

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

Pharmacology

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

Haloperidol acts on these receptors: (Ki)

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

Pharmacokinetics

By Mouth

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

Intramuscular Injections

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

Intravenous Injections

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

Therapeutic Concentrations

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

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

Distribution and Metabolism

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

Society and Culture

Cost

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

Brand Names

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

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

Veterinary Use

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

What is Phenelzine?

Published on by Andrew Marshall4 Comments

Introduction

Phenelzine, sold under the brand name Nardil, among others, is a non-selective and irreversible monoamine oxidase inhibitor (MAOI) of the hydrazine class which is used as an antidepressant and anxiolytic. Along with tranylcypromine and isocarboxazid, phenelzine is one of the few non-selective and irreversible MAOIs still in widespread clinical use. It is taken by mouth.

In June 2020, the Therapeutic Goods Administration (TGA) reported that the availability of phenelzine was discontinued in Australia due to global issues with the manufacture of the active pharmaceutical ingredient. However, unapproved phenelzine products may be accessed through alternative pathways, such as the Special Access Scheme (SAS) administered by the TGA. In October 2020, The TGA authorized two sponsors to supply an overseas-registered brand of phenelzine in Australia. In May 2020, the Specialist Pharmacy Service in the UK reported the unavailability of phenelzine from the sole supplier. In July 2020, supplies of unlicensed phenelzine 15mg capsule specials became available for UK patients. In February 2021, Phenelzine again became available in Australia as a subsidised medication through the Pharmaceutical Benefits Scheme.

Brief History

Synthesis of phenelzine was first described by Emil Votoček and Otakar Leminger in 1932.

Indications

Phenelzine is used primarily in the treatment of major depressive disorder (MDD). Patients with depressive symptomology characterised as “atypical”, “nonendogenous”, and/or “neurotic” respond particularly well to phenelzine. The medication is also useful in patients who do not respond favourably to first and second-line treatments for depression, or are “treatment-resistant”. In addition to being a recognised treatment for major depressive disorder, phenelzine is effective in treating dysthymia, bipolar depression (BD), panic disorder (PD), social anxiety disorder, bulimia, post-traumatic stress disorder (PTSD), and obsessive-compulsive disorder (OCD). Phenelzine showed promise in a phase II clinical trial from March 2020 in treating prostate cancer.

Pharmacology

Pharmacodynamics

Phenelzine is a non-selective and irreversible inhibitor of the enzyme monoamine oxidase (MAO). It inhibits both of the respective isoforms of MAO, MAO-A and MAO-B, and does so almost equally, with slight preference for the former. By inhibiting MAO, phenelzine prevents the breakdown of the monoamine neurotransmitters serotonin, melatonin, norepinephrine, epinephrine, and dopamine, as well as the trace amine neuromodulators such as phenethylamine, tyramine, octopamine, and tryptamine. This leads to an increase in the extracellular concentrations of these neurochemicals and therefore an alteration in neurochemistry and neurotransmission. This action is thought to be the primary mediator in phenelzine’s therapeutic benefits.

Phenelzine and its metabolites also inhibit at least two other enzymes to a lesser extent, of which are alanine transaminase (ALA-T), and γ-Aminobutyric acid transaminase (GABA-T), the latter of which is not caused by phenelzine itself, but by a phenelzine metabolite phenylethylidenehydrazine (PEH). By inhibiting ALA-T and GABA-T, phenelzine causes an increase in the alanine and GABA levels in the brain and body. GABA is the major inhibitory neurotransmitter in the mammalian central nervous system, and is very important for the normal suppression of anxiety, stress, and depression. Phenelzine’s action in increasing GABA concentrations may significantly contribute to its antidepressant, and especially, anxiolytic/antipanic properties, the latter of which have been considered superior to those of other antidepressants. As for ALA-T inhibition, though the consequences of disabling this enzyme are currently not well understood, there is some evidence to suggest that it is this action of the hydrazines (including phenelzine) which may be responsible for the occasional incidence of hepatitis and liver failure.

Phenelzine has also been shown to metabolise to phenethylamine (PEA). PEA acts as a releasing agent of norepinephrine and dopamine, and this occurs in the same manner as amphetamine (very similar in structure) by being taken up into vesicles, and displacing, and causing the release of those monoamines (though with markedly different pharmacokinetics such as a far shorter duration of action). Although this is indeed the same mechanism to which some (but not all) of amphetamine’s effects are attributable to, this is not all that uncommon a property among phenethylamines in general, many of which do not have psychoactive properties comparable to amphetamine. Amphetamine is different in that it binds with high affinity to the reuptake pumps of dopamine, norepinephrine, and serotonin, which phenethylamine and related molecules may as well to some extent, but with far less potency, such that it is basically insignificant in comparison. And, often being metabolized too quickly or not having the solubility to enable it to have a psychostimulant effect in humans. Claims that phenethylamine has comparable or roughly similar effects to psychostimulants such as amphetamine when administered are misconstrued. Phenethylamine does not have any obvious, easily discernible, reliably induced effects when administered to humans. Phenelzine’s enhancement of PEA levels may contribute further to its overall antidepressant effects to some degree. In addition, phenethylamine is a substrate for MAO-B, and treatment with MAOIs that inhibit MAO-B such as phenelzine have been shown to consistently and significantly elevate its concentrations.

Phenelzine usually requires six to eight weeks of treatment, and a minimum dose of 60 mg/day, to achieve therapeutic effects. The reason for the delay in therapeutic effect is not fully understood, but it is believed to be due to many factors, including achieving steady-state levels of MAO inhibition and the resulting adaptations in mean neurotransmitter levels, the possibility of necessary desensitisation of autoreceptors which normally inhibit the release of neurotransmitters like serotonin and dopamine, and also the upregulation of enzymes such as serotonin N-acetyltransferase. Typically, a therapeutic response to MAOIs is associated with an inhibition of at least 80-85% of monoamine oxidase activity.

Pharmacokinetics

Phenelzine is administered orally in the form of phenelzine sulfate and is rapidly absorbed from the gastrointestinal tract. Time to peak plasma concentration is 43 minutes and half-life is 11.6 hours. Unlike most other drugs, phenelzine irreversibly disables MAO, and as a result, it does not necessarily need to be present in the blood at all times for its effects to be sustained. Because of this, upon phenelzine treatment being ceased, its effects typically do not actually wear off until the body replenishes its enzyme stores, a process which can take as long as 2-3 weeks.

Phenelzine is metabolised primarily in the liver and its metabolites are excreted in the urine. Oxidation is the primary routine of metabolism, and the major metabolites are phenylacetic acid and parahydroxyphenylacetic acid, recovered as about 73% of the excreted dose of phenelzine in the urine over the course of 96 hours after single doses. Acetylation to N2-acetylphenelzine is a minor pathway. Phenelzine may also interact with cytochrome P450 enzymes, inactivating these enzymes through formation of a heme adduct. Two other minor metabolites of phenelzine, as mentioned above, include phenylethylidenehydrazine and phenethylamine.

Adverse Effects

Common side effects of phenelzine may include dizziness, blurry vision, dry mouth, headache, lethargy, sedation, somnolence, insomnia, anorexia, weight gain or loss, nausea and vomiting, diarrhoea, constipation, urinary retention, mydriasis, muscle tremors, hyperthermia, sweating, hypertension or hypotension, orthostatic hypotension, paraesthesia, hepatitis, and sexual dysfunction (consisting of loss of libido and anorgasmia). Rare side effects usually only seen in susceptible individuals may include hypomania or mania, psychosis and acute liver failure, the last of which is usually only seen in people with pre-existing liver damage, old age, long-term effects of alcohol consumption, or viral infection.

Interactions

The MAOIs have certain dietary restrictions and drug interactions. The amount of such restrictions and interactions is far less than previously thought, and MAOIs are generally safe medications when administered correctly. Hypertensive crisis is generally a rare occurrence while taking MAOIs, yet may result from the overconsumption of tyramine-containing foods. As a result, patients on phenelzine and other MAOIs must avoid excess quantities of certain foods that contain tyramine such as aged cheeses and cured meats, among others. Serotonin syndrome may result from an interaction with certain drugs which increase serotonin activity such as selective serotonin reuptake inhibitors, serotonin releasing agents, and serotonin agonists. Several deaths have been reported due to drug interaction-related serotonin syndrome such as the case of Libby Zion.

As is the case with other MAOIs, there is a concern regarding phenelzine and the use of both local and general anesthetics. Anyone taking phenelzine should inform their dentist before proceeding with dental surgery, and surgeon in any other contexts.

Phenelzine has also been linked to vitamin B6 deficiency. Transaminases such as GABA-transaminase have been shown to be dependent upon vitamin B6 and may be involved in a potentially related process, since the phenelzine metabolite phenylethylidenehydrazine (PEH) is a GABA transaminase inhibitor. Both phenelzine and vitamin B6 are rendered inactive upon these reactions occurring. For this reason, it may be recommended to supplement with vitamin B6 while taking phenelzine. The pyridoxine form of B6 is recommended for supplementation, since this form has been shown to reduce hydrazine toxicity from phenelzine and, in contrast, the pyridoxal form has been shown to increase the toxicity of hydrazines.

What is the Libby Zion Law?

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Introduction

New York State Department of Health Code, Section 405, also known as the Libby Zion Law, is a regulation that limits the amount of resident physicians’ work in New York State hospitals to roughly 80 hours per week. The law was named after Libby Zion, who died in 1984 at the age of 18 under the care of what her father believed to be overworked resident physicians and intern physicians. In July 2003, the Accreditation Council for Graduate Medical Education adopted similar regulations for all accredited medical training institutions in the United States.

Although regulatory and civil proceedings found conflicting evidence about Zion’s death, today her death is widely believed to have been caused by serotonin syndrome from the drug interaction between the phenelzine she was taking prior to her hospital visit, and the pethidine administered by a resident physician. The lawsuits and regulatory investigations following her death, and their implications for working conditions and supervision of interns and residents, were highly publicised in both lay media and medical journals.

Death of Libby Zion

Libby Zion (November 1965 to 05 March 1984) was a freshman at Bennington College in Bennington, Vermont. She took a prescribed antidepressant, phenelzine, daily. A hospital autopsy revealed traces of cocaine, but other later tests showed no traces. She was the daughter of Sidney Zion, a lawyer who had been a writer for The New York Times. She had two brothers, Adam and Jed. Her obituary in The New York Times, written the day after her death, stated that she had been ill with a “flu-like ailment” for the past several days. The article stated that after being admitted to New York Hospital, she died of cardiac arrest, the cause of which was not known.

Libby Zion had been admitted to the hospital through the emergency room by the resident physician assigned to the ER on the night of 04 March. Raymond Sherman, the Zion family physician, agreed with their plan to hydrate and observe her. Zion was assigned to two residents, Luise Weinstein and Gregg Stone, who both evaluated her. Weinstein, a first-year resident physician (also referred to as intern or PGY-1), and Stone, a PGY-2 resident, were unable to determine the cause of Zion’s illness, though Stone tentatively suggested that her condition might be a simple overreaction to a normal illness. After consulting with Dr. Sherman, the two prescribed pethidine (meperidine) to control the “strange jerking motions” that Zion had been exhibiting when she was admitted.

Weinstein and Stone were both responsible for covering dozens of other patients. After evaluating Zion, they left. Luise Weinstein went to cover other patients, and Stone went to sleep in an on-call room in an adjacent building. Zion, however, did not improve, and continued to become more agitated. After being contacted by nurses by phone, Weinstein ordered medical restraints be placed on Zion. She also prescribed haloperidol by phone to control the agitation.

Zion finally managed to fall asleep, but by 6:30, her temperature was 107 °F (42 °C). Weinstein was once again called, and measures were quickly taken to try to reduce her temperature. However, before this could be done, Zion had a cardiac arrest and could not be resuscitated. Weinstein informed Zion’s parents by telephone.

Several years had gone by before a general agreement was reached regarding the cause of Zion’s death. Zion had been taking a prescribed antidepressant, phenelzine, before she was admitted to the hospital. The combination of that and the pethidine given to her by Stone and Weinstein contributed to the development of serotonin syndrome, a condition which led to increased agitation. This led Zion to pull on her intravenous tubes, causing Weinstein to order physical restraints, which Zion also fought against. By the time she finally fell asleep, her fever had already reached dangerous levels, and she died soon after of cardiac arrest.

Publicity and Trials

Grieving the loss of their child, Zion’s parents became convinced their daughter’s death was due to inadequate staffing at the teaching hospital. Sidney Zion questioned the staff’s competence for two reasons. The first was the administration of pethidine, which can cause fatal interactions with phenelzine, the antidepressant that Zion was taking. Said interaction was known to few clinicians at the time, though because of this case it is now widely known. The second issue was the use of restraints and emergency psychiatric medication. Sidney’s aggrieved words were: “They gave her a drug that was destined to kill her, then ignored her except to tie her down like a dog.” To the distress of the doctors, Sidney referred to his daughter’s death as a “murder”. Sidney also questioned the long hours that residents worked at the time. In a New York Times op-ed piece, he wrote: “You don’t need kindergarten to know that a resident working a 36-hour shift is in no condition to make any kind of judgment call—forget about life-and-death.” The case eventually became a protracted high-profile legal battle, with multiple abrupt reversals; case reports about it appeared in major medical journals.

State Investigation

In May 1986, Manhattan District Attorney Robert Morgenthau agreed to let a grand jury consider murder charges, an unusual decision for a medical malpractice case. Although the jury declined to indict for murder, in 1987 the intern and resident were charged with 38 counts of gross negligence and/or gross incompetence. The grand jury considered that a series of mistakes contributed to Zion’s death, including the improper prescription of drugs and the failure to perform adequate diagnostic tests. Under New York law, the investigative body for these charges was the Hearing Committee of the State Board for Professional Medical Conduct. Between April 1987 and January 1989, the committee conducted 30 hearings at which 33 witnesses testified, including expert witnesses in toxicology, emergency medicine, and chairmen of internal medicine departments at six prominent medical schools, several of whom stated under oath that they had never heard of the interaction between meperidine and phenelzine prior to this case. At the end of these proceedings, the committee unanimously decided that none of the 38 charges against the two residents were supported by evidence. Its findings were accepted by the full board, and by the state’s Health Commissioner, David Axelrod.

Under New York law, however, the final decision in this matter rested with another body, the Board of Regents, which was under no obligation to consider either the Commissioner’s or the Hearing Committee’s recommendations. The Board of Regents, which at the time had only one physician among its 16 members, voted to “censure and reprimand” the resident physicians for acts of gross negligence. This decision did not affect their right to practice. The verdict against the two residents was considered very surprising in medical circles. In no other case had the Board of Regents overruled the Commissioner’s recommendation. The hospital also admitted it had provided inadequate care and paid a $13,000 fine to the state. In 1991, however, the state’s appeals court completely cleared the records of the two doctors of findings that they had provided inadequate care to Zion.

Civil Trial

In parallel with the state investigation, Sidney Zion also filed a separate civil case against the doctors and the hospital. The civil trial came to a close in 1995 when a Manhattan jury found that the two residents and Libby Zion’s primary care doctor contributed to her death by prescribing the wrong drug, and ordered them to pay a total of $375,000 to Zion’s family for her pain and suffering. The jury also found that Raymond Sherman, the primary care physician, had lied on the witness stand in denying he knew that Libby Zion was to be given pethidine. Although the jury found the three doctors negligent, none of them were found guilty of “wanton” negligence, i.e. demonstrating utter disregard for the patient, as opposed to a simple mistake. Payouts for wanton negligence would not have been covered by the doctors’ malpractice insurance.

The emergency room physician, Maurice Leonard, as well as the hospital (as legal persona) were found not responsible for Zion’s death in the civil trial. The jury decided that the hospital was negligent for leaving Weinstein alone in charge of 40 patients that night, but they also concluded that this negligence did not directly contribute to Zion’s death. The trial was shown on Court TV.

Law and Regulations

After the grand jury’s indictment of the two residents, Axelrod decided to address the systemic problems in residency by establishing a blue-ribbon panel of experts headed by Bertrand M. Bell, a primary care physician at the Albert Einstein College of Medicine in the Bronx. Bell was well known for his critical stance regarding the lack of supervision of physicians-in-training. Formally known as the Ad Hoc Advisory Committee on Emergency Services, and more commonly known as the Bell Commission, the committee evaluated the training and supervision of doctors in the state, and developed a series of recommendations that addressed several patient-care issues, including restraint usage, medication systems, and resident work hours.

“In 1989, New York state adopted the Bell Commission’s recommendations that residents could not work more than 80 hours a week or more than 24 consecutive hours” and that attending physicians “needed to be physically present in the hospital at all times. Hospitals instituted so-called night floats, doctors who worked overnight to spell their colleagues, allowing them to adhere to the new rules.” Periodic follow-up audits have prompted the New York State Department of Health to crack down on violating hospitals. Similar limits have since been adopted in numerous other states. In July 2003 the Accreditation Council for Graduate Medical Education (ACGME) adopted similar regulations for all accredited medical training institutions in the United States.

What is Ikigai?

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Introduction

Ikigai (生き甲斐, ‘a reason for being’) is a Japanese concept referring to something that gives a person a sense of purpose, a reason for living.

Meaning and Etymology

The Oxford English Dictionary defines ikigai, particularly with reference to Japanese culture, as “a motivating force; something or someone that gives a person a sense of purpose or a reason for living”. More generally it may refer to something that brings pleasure or fulfilment.

The term compounds two Japanese words: iki (生き, meaning ‘life; alive’) and kai (甲斐, meaning ‘(an) effect; (a) result; (a) fruit; (a) worth; (a) use; (a) benefit; (no, little) avail’) (sequentially voiced as gai), to arrive at ‘a reason for living [being alive]; a meaning for [to] life; what [something that] makes life worth living; a raison d’être’.

Overview

Ikigai can describe having a sense of purpose in life, as well as being motivated. According to a study,[vague] feeling ikigai as described in Japanese usually means the feeling of accomplishment and fulfilment that follows when people pursue their passions. Activities that allow one to feel ikigai are not forced on an individual; they are perceived as being spontaneous and undertaken willingly, therefore they are personal and depend on a person’s inner self.

According to psychologist Katsuya Inoue, ikigai is a concept consisting of two aspects: “sources or objects that bring value or meaning to life” and “a feeling that one’s life has value or meaning because of the existence of its source or object”. Inoue classifies ikigai into three directions – social ikigai, non-social ikigai, and anti-social ikigai – from a social perspective. Social ikigai refers to ikigai that are accepted by society through volunteer activities and circle activities. An asocial ikigai is an ikigai that is not directly related to society, such as faith or self-discipline. Anti-social ikigai refers to ikigai, which is the basic motivation for living through dark emotions, such as the desire to hate someone or something or to continue having a desire to revenge.

National Geographic reporter Dan Buettner suggested ikigai may be one of the reasons for the longevity of the people of Okinawa. According to Buettner, Okinawans have less desire to retire, as people continue to do their favourite job as long as they remain healthy. “Moai”, the close-knit friend group, is considered an important reason for the people of Okinawa to live long. In 2016, a book based on the concept, entitled ‘Ikigai: The Japanese Secret to a Long and Happy Life’, was published by Penguin Books, written by Héctor García and Francesc Miralles.

Early Popularisation

Although the concept of ikigai has long existed in Japanese culture, it was first popularised by Japanese psychiatrist and academic Mieko Kamiya in her 1966 book “On the Meaning of Life” (生きがいについて, ikigai ni tsuite). The book has not yet been translated into English.

Importance

In the 1960s, 1970s and 1980s, ikigai was thought to be experienced towards either the betterment of society (“subordinating one’s own desires to others”) or improvement of oneself (“following one’s own path”).

According to anthropologist Chikako Ozawa-de Silva, for an older generation in Japan, their ikigai was to “fit this standard mold of company and family”, whereas the younger generation reported their ikigai to be about “dreams of what they might become in the future”.

A 2012 study in the Global Journal of Health Science suggested that having the feeling of ikigai influenced the functioning of the frontal lobe. Some studies showed that people who do not feel ikigai are more likely to experience cardiovascular diseases. However, there was no evidence of any correlation with development of malignant tumours.

What is Play Therapy?

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Introduction

Play therapy refers to a range of methods of capitalising on children’s natural urge to explore and harnessing it to meet and respond to the developmental and later also their mental health needs.

It is also used for forensic or psychological assessment purposes where the individual is too young or too traumatised to give a verbal account of adverse, abusive or potentially criminal circumstances in their life.

Play therapy is extensively acknowledged by specialists as an effective intervention in complementing children’s personal and inter-personal development. Play and play therapy are generally employed with children aged six months through late adolescence and young adulthood. They provide a contained way for them to express their experiences and feelings through an imaginative self-expressive process in the context of a trusted relationship with the care giver or therapist. As children’s and young people’s experiences and knowledge are typically communicated through play, it is an essential vehicle for personality and social development.

In recent years play therapists in the western hemisphere, as a body of health professionals, are usually members or affiliates of professional training institutions and tend to be subject to codes of ethical practice.

Play as Therapy

According to Jean Piaget, “play provides the child with the live, dynamic, individual language indispensable for the expression of [the child’s] subjective feelings for which collective language alone is inadequate.” Play helps a child develop a sense of true self and a mastery over her/his innate abilities resulting in a sense of worth and aptitude. During play, children are driven to meet the essential need of exploring and affecting their environment. Play also contributes in the advancement of creative thinking. Play likewise provides a way for children to release strong emotions. During play, children may play out challenging life experiences by re-engineering them, thereby discharging emotional states, with the potential of integrating every experience back into stability and gaining a greater sense of mastery

General

Play therapy is a form of psychotherapy which uses play as the main mode of communication especially with children, and people whose speech capacity may be compromised, to determine and overcome psychosocial challenges. It is aimed at helping patients towards better growth and development, social integration, decreased aggression, emotional modulation, social skill development, empathy, and trauma resolution. Play therapy also assists with sensorimotor development and coping skills.

Diagnostic Tool

Play therapy can also be used as a tool for diagnosis. A play therapist observes a client playing with toys (play-houses, soft toys, dolls, etc.) to determine the cause of the disturbed behaviour. The objects and patterns of play, as well as the willingness to interact with the therapist, can be used to understand the underlying rationale for behaviour both inside and outside of therapy session. Caution, however, should be taken when using play therapy for assessment and/or diagnostic purposes.

According to the psychodynamic view, people (especially children) will engage in play behaviour to work through their interior anxieties. According to this viewpoint, play therapy can be used as a self-regulating mechanism, as long as children are allowed time for “free play” or “unstructured play.” However, some forms of therapy depart from non-directiveness in fantasy play, and introduce varying amounts of direction, during the therapy session.

An example of a more directive approach to play therapy, for example, can entail the use of a type of desensitisation or relearning therapy, to change troubling behaviours, either systematically or through a less structured approach. The hope is that through the language of symbolic play, such desensitisation may take place, as a natural part of the therapeutic experience, and lead to positive treatment outcomes.

Origins

Children’s play has been recorded in artefacts at least since antiquity. In eighteenth-century Europe, Rousseau (1712-1778) wrote, in his book Emile, about the importance of observing play as a way to learn about and understand children.

From Education to Therapeutics

During the 19th century, European educationalists began to address play as an integral part of childhood education. They include Friedrich Fröbel, Rudolf Steiner, Maria Montessori, L.S. Vygotsky, Margaret Lowenfeld, and Hans Zulliger.

Hermine Hug-Hellmuth formalised play as therapy by providing children with toys to express themselves and observed play to analyse the child. In 1919, Melanie Klein began to use play as a means of analysing children under the age of six. She believed that child’s play was essentially the same as free association used with adults, and that as such, it was provide access to the child’s unconscious. Anna Freud (1946, 1965) used play as a means to facilitate an attachment to the therapist and supposedly gain access to the child’s psyche.

Arguably, the first documented case, describing a proto-therapeutic use of play, was in 1909 when Sigmund Freud published his work with “Little Hans”, a five-year-old child suffering from a horse phobia. Freud saw him once briefly and recommended his father take note of Hans’ play to provide observations which might assist the child. The case of “Little Hans” was the first case where a child’s difficulty was adduced to emotional factors.

Models

Play therapy can be divided into two basic types: non-directive and directive. Non-directive play therapy is a non-intrusive method in which children are encouraged to play in the expectation that this will alleviate their problems as perceived by their care-givers and other adults. It is often classified as a psychodynamic therapy. In contrast, directed play therapy is a method that includes more structure and guidance by the therapist as children work through emotional and behavioural difficulties through play. It often contains a behavioural component and the process includes more prompting by the therapist. Both types of play therapy have received at least some empirical support.] On average, play therapy treatment groups, when compared to control groups, improve by .8 standard deviations.

Jessie Taft (1933), (Otto Rank’s American translator), and Frederick H. Allen (1934) developed an approach they entitled relationship therapy. The primary emphasis is placed on the emotional relationship between the therapist and the child. The focus is placed on the child’s freedom and strength to choose.

Virginia Axline, a child therapist from the 1950s applied Carl Rogers’ work to children. Rogers had explored the work of the therapist relationship and developed non-directive therapy, later called Client-Centred Therapy. Axline summarized her concept of play therapy in her article, ‘Entering the child’s world via play experiences’ and stated, “A play experience is therapeutic because it provides a secure relationship between the child and the adult, so that the child has the freedom and room to state himself in his own terms, exactly as he is at that moment in his own way and in his own time”. Axline also wrote Dibs in Search of Self, which describes a series of play therapy sessions over a period of a year.

Non-directive Play Therapy

Non-directive play therapy, may encompass child psychotherapy and unstructured play therapy. It is guided by the notion that if given the chance to speak and play freely in appropriate therapeutic conditions, troubled children and young people will be helped towards resolving their difficulties. Non-directive play therapy is generally regarded as mainly non-intrusive. The hallmark of non-directive play therapy is that it has minimal constraints apart from the frame and thus can be used at any age. These approaches to therapy may originate from Margaret Lowenfeld, Anna Freud, Donald Winnicott, Michael Fordham, Dora Kalff, all of them child specialists or even from the adult therapist, Carl Rogers’ non-directive psychotherapy and in his characterisation of “the optimal therapeutic conditions”. Virginia Axline adapted Carl Rogers’s theories to child therapy in 1946 and is widely considered the founder of this therapy. Different techniques have since been established that fall under the realm of non-directive play therapy, including traditional sandplay therapy, play therapy using provided toys and Winnicott’s Squiggle and Spatula games. Each of these forms is covered briefly below.

Using toys in non-directive play therapy with children is a method used by child psychotherapists and play therapists. These approaches are derived from the way toys were used in Anna Freud’s theoretical orientation. The idea behind this method is that children will be better able to express their feelings toward themselves and their environment through play with toys than through verbalisation of their feelings. Through this experience children may be able to achieve catharsis, gain more stability and enjoyment in their emotions, and test their own reality. Popular toys used during therapy are animals, dolls, hand puppets, soft toys, crayons, and cars. Therapists have deemed such objects as more likely to open imaginative play or creative associations, both of which are important in expression.

Sandplay

Play therapy using a tray of sand and miniature figures is attributed to Dr. Margaret Lowenfeld, a paediatrician interested in child psychology who pioneered her “World Technique” in 1929, drawn from the writer H. G. Wells and his Floor Games published in 1911. Dora Kalff, who studied with her, combined Lowenfeld’s World Technique with Jung’s idea of the collective unconscious and received Lowenfeld’s permission to name her version of the work “sandplay”. As in traditional non-directive play therapy, research has shown that allowing an individual to freely play with the sand and accompanying objects in the contained space of the sandtray (22.5″ x 28.5″) can facilitate a healing process as the unconscious expresses itself in the sand and influences the sand player. When a client creates “scenes” in the sandtray, little instruction is provided and the therapist offers little or no talk during the process. This protocol emphasises the importance of holding what Kalff referred to as the “free and protected space” to allow the unconscious to express itself in symbolic, non-verbal play. Upon completion of a tray, the client may or may not choose to talk about his or her creation, and the therapist, without the use of directives and without touching the sandtray, may offer supportive response that does not include interpretation. The rationale is that the therapist trusts and respects the process by allowing the images in the tray to exert their influence without interference.

Sandplay therapy can be used during family therapy. The limitations presented by the boundaries of the sandtray can serve as physical and symbolic limitations to families in which boundary distinctions are an issue. Also when a family works together on a sandtray, the therapist may make several observations, such as unhealthy alliances, who works with whom, which objects are selected to be incorporated into the sandtray, and who chooses which objects. A therapist may assess these choices and intervene in an effort to guide the formation of healthier relationships.

Winnicott’s Squiggle and Spatula Games

Donald Winnicott probably first came upon the central notion of play from his collaboration in wartime with the psychiatric social worker, Clare Britton, (later a psychoanalyst and his second wife), who in 1945 published an article on the importance of play for children. By “playing”, he meant not only the ways that children of all ages play, but also the way adults “play” through making art, or engaging in sports, hobbies, humour, meaningful conversation, etc. Winnicott believed that it was only in playing that people are entirely their true selves, so it followed that for psychoanalysis to be effective, it needed to serve as a mode of playing.

Two of the playing techniques Winnicott used in his work with children were the squiggle game and the spatula game. The first involved Winnicott drawing a shape for the child to play with and extend (or vice versa) – a practice extended by his followers into that of using partial interpretations as a ‘squiggle’ for a patient to make use of.

The second involved Winnicott placing a spatula (medical tongue depressor) within the child’s reach for her/him to play with. Winnicott considered that “if he is just an ordinary baby he will notice the attractive object…and he will reach for it….[then] in the course of a little while he will discover what he wants to do with it”. From the child’s initial hesitation in making use of the spatula, Winnicott derived his idea of the necessary ‘period of hesitation’ in childhood (or analysis), which makes possible a true connection to the toy, interpretation or object presented for transference.

Efficacy

Winnicott came to consider that “Playing takes place in the potential space between the baby and the mother-figure….[T]he initiation of playing is associated with the life experience of the baby who has come to trust the mother figure”. “Potential space” was Winnicott’s term for a sense of an inviting and safe interpersonal field in which one can be spontaneously playful while at the same time connected to others. Playing can also be seen in the use of a transitional object, a term Winnicott coined for an object, such as a teddy bear, which may have a quality for a small child of being both real and made-up at the same time. Winnicott pointed out that no one demands that a toddler explain whether his Binky is a “real bear” or a creation of the child’s own imagination, and went on to argue that it was very important that the child be allowed to experience the Binky as being in an undefined, “transitional” status between the child’s imagination and the real world outside the child. For Winnicott, one of the most important and precarious stages of development was in the first three years of life, when an infant grows into a child with an increasingly separate sense of self in relation to a larger world of other people. In health, the child learns to bring his or her spontaneous, real self into play with others; whereas in a False self disorder, the child may find it unsafe or impossible to do so, and instead may feel compelled to hide the true self from other people, and pretend to be whatever they want instead. Playing with a transitional object can be an important early bridge “between self and other”, which helps a child develop the capacity to be creative and genuine in relationships.

Research

Play therapy has been considered to be an established and popular mode of therapy for children for over sixty years. Critics of play therapy have questioned the effectiveness of the technique for use with children and have suggested using other interventions with greater empirical support such as Cognitive behavioural therapy (CBT). They also argue that therapists focus more on the institution of play rather than the empirical literature when conducting therapy Classically, Lebo argued against the efficacy of play therapy in 1953, and Phillips reiterated his argument again in 1985. Both claimed that play therapy lacks in several areas of hard research. Many studies included small sample sizes, which limits the generalisability, and many studies also only compared the effects of play therapy to a control group. Without a comparison to other therapies, it is difficult to determine if play therapy really is the most effective treatment. Recent play therapy researchers have worked to conduct more experimental studies with larger sample sizes, specific definitions and measures of treatment, and more direct comparisons.

Outside of the psychoanalytic child psychotherapy field, which is well annotated, research is comparatively lacking in other, or random applications, on the overall effectiveness of using toys in non-directive play therapy. Dell Lebo found that out of a sample of over 4,000 children, those who played with recommended toys vs. non-recommended or no toys during non-directive play therapy were no more likely to verbally express themselves to the therapist. Examples of recommended toys would be dolls or crayons, while example of non-recommended toys would be marbles or a checkers board game. There is also ongoing controversy in choosing toys for use in non-directive play therapy, with choices being largely made through intuition rather than through research. However, other research shows that following specific criteria when choosing toys in non-directive play therapy can make treatment more efficacious. Criteria for a desirable treatment toy include a toy that facilitates contact with the child, encourages catharsis, and lead to play that can be easily interpreted by a therapist.

Several meta analyses have shown promising results about the efficacy of non-directive play therapy. Meta analysis by authors LeBlanc and Ritchie, 2001, found an effect size of 0.66 for non-directive play therapy. This finding is comparable to the effect size of 0.71 found for psychotherapy used with children, indicating that both non-directive play and non-play therapies are almost equally effective in treating children with emotional difficulties. Meta analysis by authors Ray, Bratton, Rhine and Jones, 2001, found an even larger effect size for nondirective play therapy, with children performing at 0.93 standard deviations better than non-treatment groups. These results are stronger than previous meta-analytic results, which reported effect sizes of 0.71, 0.71, and 0.66. Meta analysis by authors Bratton, Ray, Rhine, and Jones, 2005, also found a large effect size of 0.92 for children being treated with non-directive play therapy. Results from all meta-analyses indicate that non-directive play therapy has been shown to be just as effective as psychotherapy used with children and even generates higher effect sizes in some studies

Predictors of Effectiveness

There are several predictors that may also influence the effectiveness of play therapy with children. The number of sessions is a significant predictor in post-test outcomes, with more sessions being indicative of higher effect sizes. Although positive effects can be seen with the average 16 sessions, there is a peak effect when a child can complete 35-40 sessions. An exception to this finding is children undergoing play therapy in critical-incident settings, such as hospitals and domestic violence shelters. Results from studies that looked at these children indicated a large positive effect size after only 7 sessions, which provides the implication that children in crisis may respond more readily to treatment. Parental involvement is also a significant predictor of positive play therapy results. This involvement generally entails participation in each session with the therapist and the child. Parental involvement in play therapy sessions has also been shown to diminish stress in the parent-child relationship when kids are exhibiting both internal and external behaviour problems. Despite these predictors which have been shown to increase effect sizes, play therapy has been shown to be equally effective across age, gender, and individual vs. group settings.

Directive Play Therapy

In the 1930s David Levy developed a technique he called release therapy. His technique emphasized a structured approach. A child, who had experienced a specific stressful situation, would be allowed to engage in free play. Subsequently, the therapist would introduce play materials related to the stress-evoking situation allowing the child to re-enact the traumatic event and release the associated emotions.

In 1955, Gove Hambidge expanded on Levy’s work emphasizing a “structured play therapy” model, which was more direct in introducing situations. The format of the approach was to establish rapport, recreate the stress-evoking situation, play out the situation and then free play to recover.

Directive play therapy is guided by the notion that using directives to guide the child through play will cause a faster change than is generated by nondirective play therapy. The therapist plays a much bigger role in directive play therapy. Therapists may use several techniques to engage the child, such as engaging in play with the child themselves or suggesting new topics instead of letting the child direct the conversation himself. Stories read by directive therapists are more likely to have an underlying purpose, and therapists are more likely to create interpretations of stories that children tell. In directive therapy games are generally chosen for the child, and children are given themes and character profiles when engaging in doll or puppet activities. This therapy still leaves room for free expression by the child, but it is more structured than nondirective play therapy. There are also different established techniques that are used in directive play therapy, including directed sandtray therapy and cognitive behavioural play therapy.

Directed sandtray therapy is more commonly used with trauma victims and involves the “talk” therapy to a much greater extent. Because trauma is often debilitating, directed sandplay therapy works to create change in the present, without the lengthy healing process often required in traditional sandplay therapy. This is why the role of the therapist is important in this approach. Therapists may ask clients questions about their sandtray, suggest them to change the sandtray, ask them to elaborate on why they chose particular objects to put in the tray, and on rare occasions, change the sandtray themselves. Use of directives by the therapist is very common. While traditional sandplay therapy is thought to work best in helping clients access troubling memories, directed sandtray therapy is used to help people manage their memories and the impact it has had on their lives.

Filial therapy, developed by Bernard and Louise Guerney, was an innovation in play therapy during the 1960s. The filial approach emphasizes a structured training program for parents in which they learn how to employ child-centred play sessions in the home. In the 1960s, with the advent of school counsellors, school-based play therapy began a major shift from the private sector. Counsellor-educators such as Alexander (1964); Landreth; Muro (1968); Myrick and Holdin (1971); Nelson (1966); and Waterland (1970) began to contribute significantly, especially in terms of using play therapy as both an educational and preventive tool in dealing with children’s issues.

Roger Phillips, in the early 1980s, was one of the first to suggest that combining aspects of CBT with play interventions would be a good theory to investigate. Cognitive behavioural play therapy was then developed to be used with very young children between two and six years of age. It incorporates aspects of Beck’s cognitive therapy with play therapy because children may not have the developed cognitive abilities necessary for participation in straight cognitive therapy. In this therapy, specific toys such as dolls and stuffed animals may be used to model particular cognitive strategies, such as effective coping mechanisms and problem-solving skills. Little emphasis is placed on the children’s verbalisations in these interactions but rather on their actions and their play. Creating stories with the dolls and stuffed animals is a common method used by cognitive behavioural play therapists to change children’s maladaptive thinking.

Efficacy

The efficacy of directive play therapy has been less established than that of nondirective play therapy, yet the numbers still indicate that this mode of play therapy is also effective. In 2001 meta analysis by authors Ray, Bratton, Rhine, and Jones, direct play therapy was found to have an effect size of .73 compared to the .93 effect size that nondirective play therapy was found to have. Similarly in 2005 meta analysis by authors Bratton, Ray, Rhine, and Jones, directive therapy had an effect size of 0.71, while nondirective play therapy had an effect size of 0.92. Although the effect sizes of directive therapy are statistically significantly lower than those of nondirective play therapy, they are still comparable to the effect sizes for psychotherapy used with children, demonstrated by Casey, Weisz, and LeBlanc. A potential reason for the difference in the effect size may be due to the number of studies that have been done on nondirective vs. directive play therapy. Approximately 73 studies in each meta analysis examined nondirective play therapy, while there were only 12 studies that looked at directive play therapy. Once more research is done on directive play therapy, there is potential that effect sizes between nondirective and directive play therapy will be more comparable.

Application of Electronic Games

The prevalence and popularity of video games in recent years has created a wealth of psychological studies centred around them. While the bulk of those studies have covered video game violence and addiction, some mental health practitioners in the West, are becoming interested in including such games as therapeutic tools. These are by definition “directive” tools since they are internally governed by algorithms. Since the introduction of electronic media into popular Western culture, the nature of games has become “increasingly complex, diverse, realistic, and social in nature.” The commonalities between electronic and traditional play (such as providing a safe space to work through strong emotions) infer similar benefits. Video games have been broken into two categories: “serious” games, or games developed specifically for health or learning reasons, and “off-the-shelf” games, or games without a clinical focus that may be re-purposed for a clinical setting. Use of electronic games by clinicians is a new practice, and unknown risks as well as benefits may arise as the practice becomes more mainstream.

Research

Most of the current research relating to electronic games in therapeutic settings is focused on alleviating the symptoms of depression, primarily in adolescents. However, some games have been developed specifically for children with anxiety and Attention deficit hyperactivity disorder (ADHD), The same company behind the latter intends to create electronic treatments for children on the autism spectrum, and those living with Major depressive disorder, among other disorders. The favoured approach for mental health treatment is through CBT. While this method is effective, it is not without its limitations: for example, boredom with the material, patients forgetting or not practicing techniques outside of a session, or the accessibility of care. It is these areas that therapists hope to address through the use of electronic games. Preliminary research has been done with small groups, and the conclusions drawn warrant studying the issue in greater depth.

Role-playing games (RPGs) are the most common type of electronic game used as part of therapeutic interventions. These are games where players assume roles, and outcomes depend on the actions taken by the player in a virtual world. Psychologists are able to gain insights into the elements of the capability of the patient to create or experiment with an alternate identity. There are also those who underscore the ease in the treatment process since playing an RPG as a treatment situation is often experienced as an invitation to play, which makes the process safe and without risk of exposure or embarrassment. The most well-known and well-documented RPG-style game used in treatment is SPARX. Taking place in a fantasy world, SPARX users play through seven levels, each lasting about half an hour, and each level teaching a technique to overcome depressive thoughts and behaviours. Reviews of the study have found the game treatment comparable to CBT-only therapy. However one review noted that SPARX alone is not more effective than standard CBT treatment. There are also studies that found role-playing games, when combined with the Adlerian Play Therapy (AdPT) techniques, lead to increased psychosocial development. ReachOutCentral is geared toward youth and teens, providing gamified information on the intersection of thoughts, feelings, and behaviour. An edition developed specifically to aid clinicians, ReachOutPro, offers more tools to increase patients’ engagement.

Other Applications

Biofeedback (sometimes known as applied psychophysiological feedback) media is more suited to treating a range of anxiety disorders. Biofeedback tools are able to measure heart rate, skin moisture, blood flow, and brain activity to ascertain stress levels, with a goal of teaching stress management and relaxation techniques. The development of electronic games using this equipment is still in its infancy, and thus few games are on the market. The Journey to Wild Divine’s developers have asserted that their products are a tool, not a game, though the three instalments contain many game elements. Conversely, Freeze Framer’s design is reminiscent of an Atari system. Three simplistic games are included in Freeze Framer’s 2.0 model, using psychophysiological feedback as a controller. The effectiveness of both pieces of software saw significant changes in participants’ depression levels. A biofeedback game initially designed to assist with anxiety symptoms, Relax to Win, was similarly found to have broader treatment applications. Extended Attention Span Training (EAST), developed by NASA to gauge the attention of pilots, was remodelled as an ADHD aid. Brain waves of participants were monitored during play of commercial video games available on PlayStation, and the difficulty of the games increased as participants’ attention waned. The efficacy of this treatment is comparable to traditional ADHD intervention.

Several online-only or mobile games (Re-Mission, Personal Investigator, Treasure Hunt, and Play Attention) have been specifically noted for use in alleviating disorders other than those for anxiety and mood. Re-Mission 2 especially targets children, the game having been designed with the knowledge that today’s western youth are immersed in digital media. Mobile applications for anxiety, depression, relaxation, and other areas of mental health are readily available in the Android Play Store and the Apple App Store. The proliferation of laptops, mobile phones, and tablets means one can access these apps at any time, in any place. Many of them are low-cost or even free, and the games do not need to be complex to be of benefit. Playing a three-minute game of Tetris has the potential to curb a number of cravings, a longer play time could reduce flashback symptoms from posttraumatic stress disorder, and an initial study found that a visual-spatial game such as Tetris or Candy Crush, when played closely following a traumatic event, could be used as a “‘therapeutic vaccine” to prevent future flashbacks.

Efficacy

While the field of allowing electronic media a place in a therapist’s office is new, the equipment is not necessarily so. Most western children are familiar with modern PCs, consoles, and handheld devices even if the practitioner is not. An even more recent addition to interacting with a game environment is virtual reality equipment, which both adolescent and clinician might need to learn to use properly. The umbrella term for the preliminary studies done with VR is Virtual reality exposure therapy (VRET). This research is based on traditional exposure therapy and has been found to be more effective for participants than for those placed in a wait list control group, though not as effective as in-person treatments. One study tracked two groups – one group receiving a typical, lengthier treatment while the other was treated via shorter VRET sessions – and found that the effectiveness for VRET patients was significantly less at the six-month mark.

In the future, clinicians may look forward to using electronic media as a way to assess patients, as a motivational tool, and facilitate social in-person and virtual interactions. Current data, though limited, points toward combining traditional therapy methods with electronic media for the most effective treatment.

Play Therapy in Literature

In 1953 Clark Moustakas wrote his first book, Children in Play Therapy. In 1956 he compiled Publication of The Self, the result of the dialogues between Moustakas, Abraham Maslow, Carl Rogers, and others, forging the humanistic psychology movement. In 1973 Moustakas continued his journey into play therapy and published his novel The child’s discovery of himself. Moustakas’ work as being concerned with the kind of relationship needed to make therapy a growth experience. His stages start with the child’s feelings being generally negative and as they are expressed, they become less intense, the end results tend to be the emergence of more positive feelings and more balanced relationships.

Parent/Child Play Therapy

Several approaches to play therapy have been developed for parents to use in the home with their own children.

Training in nondirective play for parents has been shown to significantly reduce mental health problems in at-risk preschool children. One of the first parent/child play therapy approaches developed was Filial Therapy (in the 1960s), in which parents are trained to facilitate nondirective play therapy sessions with their own children. Filial therapy has been shown to help children work through trauma and also resolve behaviour problems.

Another approach to play therapy that involves parents is Theraplay, which was developed in the 1970s. At first, trained therapists worked with children, but Theraplay later evolved into an approach in which parents are trained to play with their children in specific ways at home. Theraplay is based on the idea that parents can improve their children’s behaviour and also help them overcome emotional problems by engaging their children in forms of play that replicate the playful, attuned, and empathic interactions of a parent with an infant. Studies have shown that Theraplay is effective in changing children’s behaviour, especially for children suffering from attachment disorders.

In the 1980s, Stanley Greenspan developed Floortime, a comprehensive, play-based approach for parents and therapists to use with autistic children. There is evidence for the success of this program with children suffering from autistic spectrum disorders.

Lawrence J. Cohen has created an approach called Playful Parenting, in which he encourages parents to play with their children to help resolve emotional and behavioural issues. Parents are encouraged to connect playfully with their children through silliness, laughter, and roughhousing.

In 2006, Garry Landreth and Sue Bratton developed a highly researched and structured way of teaching parents to engage in therapeutic play with their children. It is based on a supervised entry level training in child centred play therapy. They named it Child Parent Relationship Therapy. These 10 sessions focus on parenting issues in a group environment and utilises video and audio recordings to help the parents receive feedback on their 30-minute ‘special play times’ with their children.

More recently, Aletha Solter has developed a comprehensive approach for parents called Attachment Play, which describes evidence-based forms of play therapy, including non-directive play, more directive symbolic play, contingency play, and several laughter-producing activities. Parents are encouraged to use these playful activities to strengthen their connection with their children, resolve discipline issues, and also help the children work through traumatic experiences such as hospitalisation or parental divorce.

What is Quetiapine?

Published on by Andrew Marshall13 Comments

Introduction

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

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

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

Brief History

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

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

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

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

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

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

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

Medical Uses

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

Schizophrenia

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

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

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

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

Bipolar Disorder

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

Major Depressive Disorder

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

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

Alzheimer’s Disease

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

Others

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

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

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

Adverse Effects

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

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

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

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

Discontinuation

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

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

Pregnancy and Lactation

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

Abuse Potential

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

Overdose

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

Pharmacology

Pharmacodynamics

Quetiapine has the following pharmacological actions:

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

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

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

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

Pharmacokinetics

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

Chemistry

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

Synthesis

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

Society and Culture

Regulatory Status

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

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

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

Lawsuits

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

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

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

Controversy

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

Nurofen Plus Tampering Case

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

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

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

What is the Alcohol Use Disorders Identification Test?

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Introduction

The Alcohol Use Disorders Identification Test (AUDIT) is a ten-item questionnaire approved by the World Health Organisation (WHO) to screen patients for hazardous (risky) and harmful alcohol consumption.

Background

It was developed from a WHO multi-country collaborative study, the items being selected for the AUDIT being the best performing of approximately 150 items including in the original survey. It is widely used as a summary measure of alcohol use and related problems. It has application in primary health care, medical clinics, and hospital units and performs well in these settings. Using different cut-off points, it can also screen for Alcohol Use Disorder (DSM-5) and Alcohol Dependence. Guidelines for the use of the AUDIT have been published by WHO and are available in several languages. It has become a widely used instrument and has been translated into approximately fifty languages.

The AUDIT consists of ten questions, all of which ask explicitly about alcohol:

  • Questions 1 to 3 ask about consumption of alcohol (frequency, quantity or typical drinking occasions, and consumption likely to cause impairment);
  • Possible dependence on alcohol (Questions 4 to 6); and
  • Harmful alcohol use, including concern expressed by others (Questions 7 to 10).

Each question is scored between 0 and 4 depending on the response and so the total score ranges between 0 and 40. Based on responses in the original WHO multi-centre study a score of 8 or more is the threshold for identifying hazardous or harmful alcohol consumption with a score of 15 or more indicating likely alcohol dependence, and 20 or more indicating likely severe dependence and harm. Using the cut-off point of 8, its performance in the original collaborative WHO study indicated a sensitivity of 92% and a specificity of 94% for the diagnoses of hazardous and harmful alcohol consumption.

The AUDIT was designed to be used internationally, and was derived from a WHO collaborative study drawing patients from six countries, representing different regions of the world and different political and economic systems. More than 300 studies have been undertaken to examine its usefulness and validity in various settings. Multiple studies have found that the AUDIT is a reliable and valid measure in identifying alcohol abuse, hazardous consumption and harmful alcohol use (consumption leading to actual harm) and it has also been found to be a valid indicator for severity of alcohol dependence. There is some evidence that the AUDIT works in adolescents and young adults; it appears less accurate in older adults. It appears well-suited for use with college students, and also with women and members of minority groups. There has also been significant evidence for its use in the trauma patient population to screen for possible alcohol use disorders. In the trauma patient population, AUDIT has been shown to be more effective at identifying possible alcohol abuse than physician judgement and the blood alcohol content (BAC) test.

A shorter version of the Alcohol Use Disorders Identification Test (AUDIT-C) has been created for rapid use, and is composed of the first 3-question of the full length AUDIT pertaining specifically to quantity of alcohol consumed. It is appropriate for screening for problem drinking in a doctor’s office.

What is a Typical Antipsychotic?

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Introduction

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

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

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

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

Brief History

The original antipsychotic drugs were happened upon largely by chance and then tested for their effectiveness. The first, chlorpromazine, was developed as a surgical anaesthetic after an initial report in 1952. It was first used in psychiatric institutions because of its powerful tranquilising effect; at the time it was regarded as a non-permanent “pharmacological lobotomy” (Note that “tranquilizing” here only refers to changes in external behaviour, while the experience a person has internally may be one of increased agitation but inability to express it).

Until the 1970s there was considerable debate within psychiatry on the most appropriate term to use to describe the new drugs. In the late 1950s the most widely used term was “neuroleptic”, followed by “major tranquilizer” and then “ataraxic”. The word neuroleptic was coined in 1955 by Delay and Deniker after their discovery (1952) of the antipsychotic effects of chlorpromazine. It is derived from the Greek: “νεῦρον” (neuron, originally meaning “sinew” but today referring to the nerves) and “λαμβάνω” (lambanō, meaning “take hold of”). Thus, the word means taking hold of one’s nerves. It was often taken to refer also to common effects such as reduced activity in general, as well as lethargy and impaired motor control. Although these effects are unpleasant and harmful, they were, along with akathisia, considered a reliable sign that the drug was working. These terms have been largely replaced by the term “antipsychotic” in medical and advertising literature, which refers to the medication’s more-marketable effects.

Clinical Uses

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

Adverse Effects

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

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

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

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

Potency

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

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

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

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

Below is list of typical antipsychotics organised by potency.

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

Long-Acting Injectables

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

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

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

On This Day … 02 August

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People (Deaths)

Paul Goodman

Paul Goodman (1911-1972) was an American author and public intellectual best known for his 1960s works of social criticism. Born to a Jewish family in New York City, Goodman was raised by his aunts and sister and attended City College of New York.

As an aspiring writer, he wrote and published poems and fiction before attending graduate school in Chicago. He returned to writing in New York City and took sporadic magazine writing and teaching jobs, many of which he lost for his outward bisexuality and World War II draft resistance. Goodman discovered anarchism and wrote for libertarian journals. He became one of the founders of gestalt therapy and took patients through the 1950s while continuing to write prolifically.

His 1960 book of social criticism, Growing Up Absurd, established his importance as a mainstream cultural theorist. Goodman became known as “the philosopher of the New Left” and his anarchistic disposition was influential in 1960s counterculture and the free school movement. His celebrity did not endure far beyond his life, but Goodman is remembered for his principles, outré proposals, and vision of human potential.