First generation antipsychotic depots

There are three first generation antipsychotic depot antipsychotic injections available in the UK. The table below lists the preparations available.^1,2,3,4,5,6

All first generation depot antipsychotics are esterified long chain fatty acids contained in a base oil. Once injected the ester bond is gradually broken down releasing active drug into the blood stream.

There is little evidence to suggest any significant differences in efficacy between the three available drugs. The main differences are in relative side effects.

• Haloperidol is more commonly associated with extra-pyramidal side effects (EPSE), acute dystonic reactions (torticollis, facial grimacing, trismus, tongue protrusion, and abnormal eye movements, including oculogyric crisis) can occur within the first few days of treatment and may necessitate stopping treatment.
• Zuclopenthixol may be more effective at preventing relapse than the others.⁷
• Flupentixol is probably less sedating.⁶

When prescribing first generation depot antipsychotics, administering a test dose is essential for two reasons:

• Firstly, to determine the sensitivity of the patient to extrapyramidal side effects (EPSE)
• Secondly, to test sensitivity to the base oil.

After giving the test dose monitor the patient closely over the next 4–10 days for any reaction to the base oil and the emergence of EPSE. If any reaction or side effects occur do not proceed with treatment doses. Note; hypersensitivity and anaphylaxis are rare side effects of depot antipsychotics.^3,4,5

The next table lists the recommended test dose for each drug.

^a The SPC for haloperidol does not recommend a test dose therefore a test dose of 25mg is suggested.

If the test dose is tolerated, active treatment can then commence. The following principles should be applied:

1. Begin with the lowest therapeutic dose and titrate slowly to the minimum effective dose. Lower doses may be as effective as the higher end of the dose range and are likely to be better tolerated. This is especially true with flupentixol decanoate where standard doses are as effective as high doses.⁸

2. Administer at the longest possible licensed interval to begin with as this reduces the potential medicine burden and minimises the number of injections required.

3. Adjust doses only after an adequate period of assessment. Clearly with depot antipsychotics the pharmacokinetics of the drug is significantly altered due to the sustained action. Peak plasma levels, therapeutic effect and steady state plasma levels are all delayed. At the start of treatment the plasma levels of the antipsychotic released from a depot increase over several weeks or months without increasing the given dose due to accumulation. Steady state therefore may take up to 12 weeks to achieve. Dose increases during this period are therefore illogical but may be driven by practical necessity. It is recommended that after the initial treatment dose a minimum of 2 further doses should be administered before any dose increase is considered. During this period the patient should be assessed for response, side effects and physical health impact.

The following table illustrates the dose range and time to steady state for the first generation depot antipsychotics.

The time delays with depot treatment can cause practical management difficulties but pressures to increase doses more rapidly should be resisted in the interest of achieving treatment with the lowest possible effective dose at the maximum possible interval.

In addition to the known side effects associated with phenothiazine and thioxanthene antipsychotics (EPSE, sedation, antimuscarinic effects, sexual dysfunction) injection site reactions are possible.

Long term use can lead to scarring and nodule formation however this can be minimised by good injection technique and rotation of the injection site.

Discontinuation of depot antipsychotics is straightforward. Withdrawal reactions are unlikely as active drug persists in the body for 3 – 6 months after discontinuation.

Changing antipsychotic is more problematic. The extended half-life of these preparations means the potential for significant interactions when swapping treatments needs careful consideration. Whether it involves swapping from one depot to another or from a depot to an oral treatment, factors to consider include:

• The dose and frequency of administration of the current drug
• The length of time on treatment
• If swapping from a first generation depot to oral treatment, titrate up to an approximately equivalent oral dose when the depot is next due
• When swapping from one first generation depot to another, there is still the requirement to administer a test dose. The test dose should be administered on the day the previous depot was due. The dose should then be titrated cautiously bearing in mind the previous depot will still be present
• Please contact mental health clinical pharmacy services for advice regarding switches
• It is important to be aware of the potential for cumulative side effects with the delayed clearance of the original depot and the introduction of the new antipsychotic

It is important to provide patients with appropriate information prior to and throughout treatment with first generation depot antipsychotics.

The specific drug leaflets from Choice and Medication are recommended.

1. Taylor D, Paton C, Kapur S. The Maudsley Prescribing Guidelines in Psychiatry; 13th Edition: Wiley Blackwell
2. Bazire S. Psychotropic Drug Directory 2016; Lloyd-Reinhold Publications
3. Janssen-Cilag Haldol decanoate 100mg/ml Summary of Product Characteristics. Last updated 14/5/19, accessed online 28/4/20 www.medicines.org.uk/emc
4. Lundbeck Depixol Conc. 100mg/ml Summary of Product Characteristics. Last updated 6/4/17, accessed online 28/4/20 www.medicines.org.uk/emc 
5. Lundbeck Clopixol 200mg/ml Summary of Product Characteristics. Last updated 26/1/17, accessed online 28/4/20 www.medicines.org.uk/emc
6. BNF British National Formulary. Accessed online 28/4/20
7. da Silva Freire Coutinho E, Fenton M, Quraishi SN. Zuclopenthixol decanoate for schizophrenia and other serious mental illnesses. Cochrane Database of Systematic Reviews 1999, Issue 3. Art. No.: CD001164. DOI: 10.1002/14651858.CD001164.
8. Mahapatra J, Quraishi SN, David A, Sampson S, Adams CE. Flupenthixol decanoate (depot) for schizophrenia or other similar psychotic disorders. Cochrane Database of Systematic Reviews 2014, Issue 6. Art. No.: CD001470. DOI: 10.1002/14651858.CD001470.pub2.