What is Perphenazine?

Introduction

Perphenazine is a typical antipsychotic drug. Chemically, it is classified as a piperazinyl phenothiazine. Originally marketed in the United States as Trilafon, it has been in clinical use for decades.

Perphenazine is roughly ten times as potent as chlorpromazine at the dopamine-2 (D2) receptor; thus perphenazine is considered a medium-potency antipsychotic.

Medical Uses

In low doses it is used to treat agitated depression (together with an antidepressant). Fixed combinations of perphenazine and the tricyclic antidepressant amitriptyline in different proportions of weight exist (see Etrafon below). When treating depression, perphenazine is discontinued as fast as the clinical situation allows. Perphenazine has no intrinsic antidepressive activity. Several studies show that the use of perphenazine with fluoxetine (Prozac) in patients with psychotic depression is most promising, although fluoxetine interferes with the metabolism of perphenazine, causing higher plasma levels of perphenazine and a longer half-life. In this combination the strong antiemetic action of perphenazine attenuates fluoxetine-induced nausea and vomiting (emesis), as well as the initial agitation caused by fluoxetine. Both actions can be helpful for many patients.

Perphenazine has been used in low doses as a ‘normal’ or ‘minor’ tranquiliser in patients with a known history of addiction to drugs or alcohol, a practice which is now strongly discouraged.

Perphenazine has sedating and anxiolytic properties, making the drug useful for the treatment of agitated psychotic patients.

A valuable off-label indication is the short-time treatment of hyperemesis gravidarum, in which pregnant women experience violent nausea and vomiting. This problem can become severe enough to endanger the pregnancy. As perphenazine has not been shown to be teratogenic and works very well, it is sometimes given orally in the smallest possible dose.

Effectiveness

Perphenazine is used to treat psychosis (e.g. in people with schizophrenia and the manic phases of bipolar disorder). Perphenazine effectively treats the positive symptoms of schizophrenia, such as hallucinations and delusions, but its effectiveness in treating the negative symptoms of schizophrenia, such as flattened affect and poverty of speech, is unclear. Earlier studies found the typical antipsychotics to be ineffective or poorly effective in the treatment of negative symptoms, but two recent, large-scale studies found no difference between perphenazine and the atypical antipsychotics.

Side Effects

As a member of the phenothiazine type of antipsychotics, perphenazine shares in general all allergic and toxic side-effects of chlorpromazine. A 2015 systematic review of the data on perphenazine conducted by the Cochrane Collaboration concluded that “there were no convincing differences between perphenazine and other antipsychotics” in the incidence of adverse effects. Perphenazine causes early and late extrapyramidal side effects more often than placebo, and at a similar rate to other medium-potency antipsychotics and the atypical antipsychotic risperidone.

When used for its strong antiemetic or antivertignosic effects in cases with associated brain injuries, it may obscure the clinical course and interferes with the diagnosis. High doses of perphenazine can cause temporary dyskinesia. As with other typical antipsychotics, permanent or lasting tardive dyskinesia is a risk.

Discontinuation

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

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

Pharmacology

Pharmacokinetics

Perphenazine has an oral bioavailability of approximately 40% and a half-life of 8 to 12 hours (up to 20 hours), and is usually given in 2 or 3 divided doses each day. It is possible to give two-thirds of the daily dose at bedtime and one-third during breakfast to maximise hypnotic activity during the night and to minimise daytime sedation and hypotension without loss of therapeutic activity.

Formulations

It is sold under the brand names Trilafon (single drug) and Etrafon/Triavil/Triptafen (contains fixed dosages of amitriptyline). A brand name in Europe is Decentan pointing to the fact that perphenazine is approximately 10-times more potent than chlorpromazine. Usual oral forms are tablets (2, 4, 8, 16 mg) and liquid concentrate (4 mg/ml).

The ‘Perphenazine injectable USP’ solution is intended for deep intramuscular (IM) injection, for patients who are not willing to take oral medication or if the patient is unable to swallow. Due to a better bioavailability of the injection, two-thirds of the original oral dose is sufficient. The incidence of hypotension, sedation and extrapyramidal side-effects may be higher compared to oral treatment. IM-injections are appropriate for a few days, but oral treatment should start as soon as possible.

In many countries, depot forms of perphenazine exist (as perphenazine enanthate and perphenazine decanoate). One injection works for 1 to 4 weeks depending on the dose of the depot-injection. Depot-forms of perphenazine should not be used during the initial phase of treatment as the rare neuroleptic malignant syndrome may become more severe and uncontrollable with this form. Extrapyramidal side-effects may be somewhat reduced due to constant plasma-levels during depot-therapy. Also, patient compliance is sure, as many patients do not take their oral medication, particularly if feeling better once improvement in psychosis is achieved.

Interactions

Fluoxetine causes higher plasma levels and a longer elimination half-life of perphenazine, therefore a dose reduction of perphenazine might be necessary.

Perphenazine intensifies the central depressive action of drugs with such activity (tranquilizers, hypnotics, narcotics, antihistaminics, OTC-antiemetics etc.). A dose reduction of perphenazine or the other drug may be necessary.

In general, all neuroleptics may lead to seizures in combination with the opioid tramadol (Ultram).

Perphenazine may increase the insulin needs of diabetic patients. Monitor blood glucose levels of insulin-dependent patients regularly during long-term treatment.

What is a Typical Antipsychotic?

Introduction

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

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

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

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

Brief History

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

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

Clinical Uses

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

Adverse Effects

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

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

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

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

Potency

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

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

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

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

Below is list of typical antipsychotics organised by potency.

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

Long-Acting Injectables

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

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

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