Flupentixol

Flupentixol (INN), also known as flupenthixol (former BAN), marketed under brand names such as Depixol and Fluanxol is a typical antipsychotic drug of the thioxanthene class. It was introduced in 1965 by Lundbeck. In addition to single drug preparations, it is also available as flupentixol/melitracen—a combination product containing both melitracen (a tricyclic antidepressant) and flupentixol (marketed as Deanxit).
Flupentixol is not approved for use in the United States. It is, however, approved for use in the UK, Australia, Canada, Russian Federation, South Africa, New Zealand, Philippines, Iran, Germany, and various other countries.
Medical uses
Flupentixol's main use is as a long-acting injection given once in every two or three weeks to individuals with schizophrenia who have poor compliance with medication and have frequent relapses of illness, though it is also commonly given as a tablet. There is little formal evidence to support its use for this indication but it has been in use for over fifty years.
Flupentixol is also used in low doses as an antidepressant. There is tentative evidence that it reduces the rate of deliberate self-harm, among those who self-harm repeatedly.
Adverse effects
Adverse effect incidence
Common (>1% incidence) adverse effects include
Extrapyramidal side effects such as: (which usually become apparent soon after therapy is begun or soon after an increase in dose is made)
Muscle rigidity
Hypokinesia
Hyperkinesia
Parkinsonism
Tremor
Akathisia
Dystonia
Dry mouth
Constipation
Hypersalivation – excessive salivation
Blurred vision
Diaphoresis – excessive sweating
Nausea
Dizziness
Somnolence
Restlessness
Insomnia
Overactivity
Headache
Nervousness
Fatigue
Myalgia
Hyperprolactinemia and its complications such as: (acutely)
Sexual dysfunction
Amenorrhea – cessation of menstrual cycles
Gynecomastia – enlargement of breast tissue in males
Galactorrhea – the expulsion of breast milk that's not related to breastfeeding or pregnancy
and if the hyperprolactinemia persists chronically, the following adverse effects may be seen:
Reduced bone mineral density leading to osteoporosis (brittle bones)
Infertility
Dyspepsia – indigestion
Abdominal pain
Flatulence
Nasal congestion
Polyuria – passing more urine than usual
Uncommon (0.1–1% incidence) adverse effects include
Fainting
Palpitations
Rare (<0.1% incidence) adverse effects include
Blood dyscrasias (abnormalities in the cell composition of blood), such as:
Agranulocytosis – a drop in white blood cell counts that leaves one open to potentially life-threatening infections
Neutropenia – a drop in the number of neutrophils (white blood cells that specifically fight bacteria) in one's blood
Leucopenia – a less severe drop in white blood cell counts than agranulocytosis
Thrombocytopenia – a drop in the number of platelets in the blood. Platelets are responsible for blood clotting and hence this leads to an increased risk of bruising and other bleeds
Neuroleptic malignant syndrome – a potentially fatal condition that appear to result from central D2 receptor blockade. The symptoms include:
Hyperthermia
Muscle rigidity
Rhabdomyolysis
Autonomic instability (e.g. tachycardia, diarrhea, diaphoresis, etc.)
Mental status changes (e.g. coma, agitation, anxiety, confusion, etc.)
Unknown incidence adverse effects include
Jaundice
Abnormal liver function test results
Tardive dyskinesia – an often incurable movement disorder that usually results from years of continuous treatment with antipsychotic drugs, especially typical antipsychotics like flupenthixol. It presents with repetitive, involuntary, purposeless and slow movements; TD can be triggered by a fast dose reduction in any antipsychotic.
Hypotension
Confusional state
Seizures
Mania
Hypomania
Depression
Hot flush
Anergia
Appetite changes
Weight changes
Hyperglycemia – high blood glucose (sugar) levels
Abnormal glucose tolerance
Pruritus – itchiness
Rash
Dermatitis
Photosensitivity – sensitivity to light
Oculogyric crisis
Accommodation disorder
Sleep disorder
Impaired concentration
Tachycardia
QTc interval prolongation – an abnormality in the electrical activity of the heart that can lead to potentially fatal changes in heart rhythm (only in overdose or <10 ms increases in QTc)
Torsades de pointes
Miosis – constriction of the pupil of the eye
Paralytic ileus – paralysis of the bowel muscles leading to severe constipation, inability to pass wind, etc.
Mydriasis
Glaucoma
Interactions
It should not be used concomitantly with medications known to prolong the QTc interval (e.g. 5-HT3 antagonists, tricyclic antidepressants, citalopram, etc.) as this may lead to an increased risk of QTc interval prolongation. Neither should it be given concurrently with lithium (medication) as it may increase the risk of lithium toxicity and neuroleptic malignant syndrome. It should not be given concurrently with other antipsychotics due to the potential for this to increase the risk of side effects, especially neurological side effects such as neuroleptic malignant syndrome. It should be avoided in patients on CNS depressants such as opioids, alcohol and barbiturates.
Contraindications
It should not be given in the following disease states:
Pheochromocytoma
Prolactin-dependent tumors such as pituitary prolactinomas and breast cancer
Long QT syndrome
Coma
Circulatory collapse
Subcortical brain damage
Blood dyscrasia
Parkinson's disease
Dementia with Lewy bodies
Pharmacology
Pharmacodynamics
Binding profile
Acronyms used:
HFC – Human frontal cortex receptor
MB – Mouse brain receptor
RC – Cloned rat receptor
A study measuring the in vivo receptor occupancies of 13 schizophrenic patients treated with 5.7 ± 1.4 mg/day of flupentixol found 50-70% receptor occupancy for D2, 20 ± 5% for D1, and 20 ± 10% for 5-HT2A.
Its antipsychotic effects are predominantly a function of D2 antagonism.
Its antidepressant effects at lower doses are not well understood; however, it may be mediated by functional selectivity and/or preferentially binding to D2 autoreceptors at low doses, resulting in increased postsynaptic activation via higher dopamine levels. Flupentixol's demonstrated ability to raise dopamine levels in mice and flies lends credibility to the supposition of autoreceptor bias. Functional selectivity may be responsible through causing preferential autoreceptor binding or other means. The effective dosage guideline for an antipsychotic is very closely related to its receptor residency time (i.e. where drugs like aripiprazole take several minutes or more to disassociate from a receptor while drugs like quetiapine and clozapine—with guideline dosages in the hundreds of milligrams—take under 30s) and long receptor residency time is strongly correlated with likehood of pronounced functional selectivity; thus, with a maximum guideline dose of only 18 mg/day for schizophrenia, there is a significant possibility of this drug possessing unique signalling characteristics that permit counterintuitive dopaminergic action at low doses.
Pharmacokinetics
History
In March 1963 the Danish pharmaceutical company Lundbeck began research into further agents for schizophrenia, having already developed the thioxanthene derivatives clopenthixol and chlorprothixene. By 1965 the promising agent flupenthixol had been developed and trialled in two hospitals in Vienna by Austrian psychiatrist Heinrich Gross. The long- acting decanoate preparation was synthesised in 1967 and introduced into hospital practice in Sweden in 1968, with a reduction in relapses among patients who were put on the depot.
References
Typical antipsychotics
Antidepressants
Trifluoromethyl compounds
Piperazines
Thioxanthene antipsychotics