• Classification of antipsychotics
  • Newer agents like pimavanserin and xanomeline possess antipsychotic activity and do not cause EPS, yet they share minimal commonalities with other atypical antipsychotics regarding chemistry, pharmacology, or their adverse-effect profiles.

• Relative efficacy
  • In the longer term, olanzapine may demonstrate advantages compared to certain other antipsychotic medications.
• Long-Acting Injectables (LAIs)
  • While substantial evidence indicates that depot/LAI preparations are linked to a decreased risk of relapse and rehospitalisation compared to oral antipsychotics, it is noted that RCTs do not consistently mirror this difference.
  • A logical evaluation of LAI benefits and the negative impact of relapse supports the consideration of LAIs as first-line treatments, rather than reserving them for individuals who have already experienced relapse while on oral medication.
• Treatment Resistance
  • For patients whose symptoms have not adequately responded to sequential trials of two or more antipsychotics, clozapine is the most effective treatment. Its use in these situations is recommended not only by NICE but likely by every other schizophrenia guideline as well.

• Dose increases should take place only after 1–2 weeks of assessment, during which the patient is clearly showing poor or no response.
• Antipsychotic LAIs provide better relapse protection than oral treatment. LAIs should be used as first-line treatment aimed at preventing relapse. They should not be reserved only for those who have already relapsed on oral treatment.
• Clozapine should be offered as soon as treatment resistance is apparent. The sooner clozapine is prescribed, the more effective it will be.
• Apart from some exceptional circumstances (e.g. clozapine augmentation or adjunctive aripiprazole for prolactin elevation) antipsychotic polypharmacy should generally be avoided because of the increased adverse-effect burden and risks associated with QT prolongation and sudden cardiac death (see section on antipsychotic polypharmacy in this chapter).
• Time-limited prescriptions of benzodiazepines or general sedatives (e.g. promethazine) are preferred.

Antipsychotics – minimum effective doses

The minimum dose likely to be effective varies for first- or multi-episode schizophrenia. Most patients respond to suggested doses, but some may need higher doses. Due to individual response variations, all doses are approximate. Only oral treatment with commonly used drugs is covered here.

• Asenapine: Minimum effective dose/day is estimated at 5mg for first episode and 10mg for multi-episode.
• Clotiapine: Minimum effective dose/day is not known for first episode and 120mg for multi-episode.
• Quetiapine: Minimum effective dose/day is estimated at 150mg for first episode (though higher doses are often used). For multi-episode, it is 300mg IR or 500mg MR.
• Xanomeline: Minimum effective dose/day is estimated at 200mg for both first episode and multi-episode.
• Pimavanserin: US Food and Drug Administration-approved for Parkinson’s disease psychosis; the dose in schizophrenia is not clear (minimum effective dose estimated at 34mg, episode type not specified).

Efficacy

• The prescription of high-dose antipsychotic medication remains relatively common in clinical practice.
• A 2022 UK audit of adult inpatients in mental health services indicated that just under 10% of over 4,000 patients on acute adult wards were prescribed high-dose antipsychotics. For over 2,000 patients on forensic wards, this figure was 13%. In both settings, high-dose prescriptions were mainly due to combined antipsychotic use.
• Regarding TRS, subsequent systematic reviews assessing high-dose olanzapine have concluded that while such a regimen might be superior to other non-clozapine antipsychotics, it should primarily be considered a safe and effective alternative only when clozapine use is not appropriate.
• Consensus panel recommendations generally align with clinical trial data. A 2023 international consensus study suggested maximum effective doses exceeded licensed doses only for olanzapine (30mg/day) and quetiapine (800mg/day).
• A 2023 systematic review analyzing dose–response relationships found that the effect of all antipsychotics reached a plateau within their licensed dose range, with potential exceptions noted for lumateperone, olanzapine, and lurasidone.

Adverse effects

• Weight gain is among the adverse effects associated with antipsychotic treatment that are dose-related.

Prescribing high-dose antipsychotic medication

• Before resorting to high doses, ensure that clozapine has failed or was not tolerated due to agranulocytosis or other serious adverse effects. It's important to note that most other adverse effects associated with clozapine can typically be managed. A patient may also decline to take clozapine.

First episode of psychosis

• Studies confirm that only a small fraction of patients discontinuing medication after a first episode remain well long-term. For instance, one small study indicated that 97% of patients relapsed within three years of stopping risperidone long-acting injection.
• There are indications that using very prolonged discontinuation schedules involving hyperbolic tapering may provide the best opportunity for successfully withdrawing from antipsychotic treatment.
• It's important to recognise that definitions of relapse typically concentrate on the severity of positive symptoms. These positive symptoms are more frequently the cause of hospitalisation. Conversely, cognitive and negative symptoms, which tend to respond less effectively to antipsychotic treatment and may sometimes be worsened by it, have a more significant overall effect on a person's quality of life.
• When attempting gradual dose reduction, ensuring awareness among relevant family members and healthcare staff is crucial. Utilising a LAI formulation is often the most practical way to achieve this monitored situation.

Multi-episode schizophrenia

• The optimal dosage for preventing relapse is equivalent to 5mg/day of risperidone. Prescribing higher doses does not offer additional benefits and leads to poorer tolerability.
• Long-acting depot preparations might hold an advantage over oral medications in maintenance treatment.
• The observed advantage for olanzapine in achieving remission, as noted in studies like CATIE, is further supported by findings from two recent meta-analyses focusing on long-term efficacy.

Adherence to antipsychotic treatment

• Given the consistently low rates of adherence observed in patients with schizophrenia and the high likelihood of relapse when antipsychotics are not taken, the routine use of oral antipsychotics becomes difficult to justify from a clinical standpoint.

Dose for prophylaxis

• Data from a large meta-analysis clearly indicates that the effectiveness of antipsychotics in preventing relapse begins to decrease at doses below approximately 5mg/day risperidone equivalents.
• The approach of guided antipsychotic dose reduction has received more attention recently, spurred partly by the apparent success reported in the Wunderink study. However, subsequent studies suggest that guided dose reduction carries a significantly higher risk of relapse compared to continuing treatment at standard doses.
• Importantly, even with guided dose reduction or complete cessation of treatment, not all individuals experience relapse, at least within the observation periods of the studies conducted. This suggests that a subset of individuals, likely a small minority, may be capable of stopping antipsychotic medication without relapsing.

• While there is some consensus around the two-dimensional model of negative symptoms (expressive deficits and avolition/amotivation), five-factor models have also been proposed.
• In individuals with established schizophrenia, prominent, clinically relevant negative symptoms are observed in approximately 60%.

Pharmacological treatment of negative symptoms

• There are relatively robust data indicating superior efficacy for negative symptoms with certain antipsychotics, including cariprazine, aripiprazole, and amisulpride.
• A 2023 review identified amisulpride and cariprazine as having significant promise for treating primary negative symptoms.
• For patients treated with clozapine who experience residual negative symptoms, evidence suggests that adding cariprazine may be beneficial.
• Regarding the effect of decreasing glutamate transmission, three meta-analyses have suggested a beneficial response with add-on memantine.
• Although initial studies of adding minocycline showed promise, a relatively large RCT found it was not effective in treating negative symptoms, and the BeneMin study also failed to demonstrate clinical benefit when used early in the illness course to prevent negative symptom development.
• Other augmentation agents tested include:
  • Palmitoylethanolamide (added to risperidone).
  • Pimavanserin (a potent 5-HT2A inverse agonist and antagonist).
  • Roluperidone (a 5HT2 antagonist) may also be effective.
• Other experimental treatments with promising data include:
  • Pregnenolone
  • Raloxifene (in women)
  • Levetiracetam
  • Clonidine
  • Nanocurcumin
  • Xanomeline (as Cobenfy)
  • The anti-inflammatory drugs berberine and fingolimod.
• tDCS may hold some potential as a treatment, but current evidence is limited and somewhat inconsistent.

Further details and discussion on monitoring can be found in the individual sections relevant to each specific parameter or test.

• FBC
  • If neutrophil levels fall below 1.5×10⁹/L, the suspected medication should be stopped, unless the individual has a diagnosis of BEN.
• Blood Lipids
  • Antipsychotic medications such as brexpiprazole and cariprazine are not clearly associated with dyslipidaemia, although monitoring is still advised due to the high prevalence in this patient group.
• Weight
  • Even for antipsychotics not clearly associated with weight gain (like aripiprazole, ziprasidone, brexpiprazole, cariprazine, and lurasidone), monitoring is strongly recommended.
• ECG
  • An ECG should be considered if the patient develops cardiac symptoms, or when medication changes occur, such as initiating high-dose or combined antipsychotic regimens.
  • An ECG is strongly recommended for patients taking pimavanserin.
• Blood Pressure
  • Hypertension should be treated in line with relevant national guidelines.
  • Lumateperone is among the antipsychotics less likely to be associated with postural hypotension.
• Prolactin
  • Lumateperone and xanomeline usually do not elevate plasma prolactin levels.
  • Olanzapine at low doses generally does not elevate plasma prolactin.
• CPK
  • NMS is most commonly associated with high-potency FGAs, but it can potentially occur with any dopamine antagonist or partial agonist medication.
• Other Tests
  • For patients taking clozapine, an EEG may help in determining the necessity for antiseizure treatment.

• Antipsychotic adverse effect profiles now include consideration for the risk of Prolonged QT interval.

Newly included agents and their general adverse effect profiles are:

• Blonanserin: Very low/zero sedation, weight gain, anticholinergic effects, hypotension, prolonged QT; Low akathisia, prolactin elevation; Moderate parkinsonism.
• Levomepromazine: High sedation, anticholinergic effects, hypotension; Low weight gain, akathisia, parkinsonism, prolactin elevation, prolonged QT.
• Penfluridol: Very low/zero sedation; Moderate weight gain, akathisia, parkinsonism, anticholinergic effects, prolonged QT; High prolactin elevation; Low hypotension.
• Thiothixene: Moderate sedation, weight gain, parkinsonism, anticholinergic effects, hypotension, prolactin elevation; Low akathisia, prolonged QT.
• Xanomeline: Very low/zero sedation, weight gain, akathisia, parkinsonism, anticholinergic effects, hypotension, prolactin elevation; Low prolonged QT.

Updates to relative adverse effect estimates for previously listed drugs include:

• Aripiprazole: Now rated Low (+) for weight gain (previously Very low/zero).
• Asenapine: Now rated Low (+) for parkinsonism (previously Very low/zero).
• Brexpiprazole: Now rated Low (+) for weight gain (previously Very low/zero).
• Cariprazine: Now rated Low (+) for weight gain (previously Very low/zero).
• Haloperidol: Now rated Very low/zero (-) for anticholinergic effects (previously Low).
• Loxapine: Now rated Moderate (++) for parkinsonism (previously High).
• Lurasidone: Now rated Low (+) for weight gain (previously Very low/zero).
• Olanzapine: Now rated High (+++) for sedation (previously Moderate); Low (+) for akathisia (previously Very low/zero).
• Paliperidone: Now rated Moderate (++) for akathisia (previously Low); Very low/zero (-) for anticholinergic effects (previously Low).
• Pimozide: Now rated Moderate (++) for weight gain, akathisia, parkinsonism, and anticholinergic effects (all previously Low).
• Quetiapine: Now rated High (+++) for sedation (previously Moderate); Low (+) for akathisia (previously Very low/zero).
• Risperidone: Now rated Moderate (++) for akathisia (previously Low); Very low/zero (-) for anticholinergic effects (previously Low).

QT Prolongation Risk Estimates Added:

• High (+++): Clozapine, Pimozide, Sertindole.
• Moderate (++): Amisulpride, Chlorpromazine, Haloperidol, Iloperidone, Pimavanserin, Promazine, Quetiapine, Ziprasidone, Penfluridol.
• Low (+): Benperidol, Fluphenazine, Levomepromazine, Olanzapine, Paliperidone, Perphenazine, Risperidone, Sulpiride, Zuclopenthixol, Thiothixene, Xanomeline.
• Very low/zero (-): Aripiprazole, Asenapine, Blonanserin, Brexpiprazole, Cariprazine, Flupentixol, Lumateperone, Loxapine, Lurasidone.
• Unknown (?): Trifluoperazine.

First-episode schizophrenia

• When patient agreement on antipsychotic choice isn't possible, the initial selection of a second-generation antipsychotic should preferably be one that is available in a LAI formulation.
• After establishing effectiveness and tolerability with an oral antipsychotic, a key step is to switch to the LAI formulation. This is also an option if poor adherence or tolerability occurs.
• Regarding clozapine use for non-response: Delaying the initiation of clozapine diminishes the potential response to it.

Relapse or acute exacerbation of schizophrenia (full adherence to medication confirmed)

• Even when adherence is thought to be confirmed, it's important to note that non-compliance often goes undetected in patients taking oral antipsychotics. Absolute non-compliance (zero drug levels) can be surprisingly common.

Relapse or acute exacerbation of schizophrenia (adherence doubtful or known to be poor)

• If switching antipsychotics due to poor tolerability, use the LAI formulation if the patient agrees.

Nomenclature

• While NbN offers an alternative to FGA/SGA classification by describing drugs based on pharmacological activity, a potential limitation exists. NbN preselects specific pharmacological features based on expert opinion about their importance to drug action, potentially overlooking other factors, especially since the exact mechanisms of action remain unknown.
• In 2023, a different classification approach based on in vitro binding profiles was proposed. This data-driven method identified four distinct clusters of effects:
  1. High affinity for muscarinic receptors (e.g., olanzapine, quetiapine).
  2. Relatively low antagonism of the dopamine D2 receptor (e.g., partial agonists, lurasidone).
  3. Serotonergic antagonism (e.g., risperidone).
  4. Relatively pure dopaminergic antagonism (e.g., amisulpride).
• These clusters demonstrated a more accurate mapping to adverse-effect profiles compared to other classification systems.
• A potential drawback of this data-driven approach is that it assigns an equal level of importance to all receptors, regardless of the magnitude of their impact on clinically relevant effects.
• Wider use of either NbN or the data-driven approach may improve understanding of individual drug effects and help prevent future redundant categorisation.

Role of older antipsychotics

• The main drawbacks of FGAs include acute EPS, hyperprolactinaemia, and TD.
• TD very probably occurs more frequently with FGAs than SGAs, although some uncertainty persists, and the dose of FGA used is a critical factor.
• A complicating aspect is the occurrence of TD in untreated schizophrenia. This observation suggests that antipsychotics might not necessarily be the sole cause of TD but could, to varying degrees, simply fail to suppress it.
• Among SGAs, partial agonists may possess the lowest risk of TD. Careful observation of patients and the prescribing of the lowest effective dose are essential strategies to help mitigate the risk of this serious adverse event.

• The UK NICE guidelines were published in February 2014 and last reviewed in September 2024, remaining largely unchanged.

First-episode psychosis

• Before initiating antipsychotic medication, conduct a thorough assessment of physical health.
• Offer an ECG if specified in the SPC or if clinically indicated.
• Monitor and record adverse effects of treatment, recognizing the overlap between certain adverse effects and clinical features (e.g., akathisia and agitation/anxiety).

Subsequent episodes of psychosis/maintenance treatment of schizophrenia

• Consider the clinical response and adverse effects associated with the service user’s current and previous medication.
• GPs and other primary healthcare professionals should monitor the physical health of individuals with psychosis or schizophrenia when responsibility is first transferred from secondary care, and subsequently at least on an annual basis.
• This health check should be comprehensive, specifically focusing on physical health problems commonly found in people with psychosis and schizophrenia.

Treatment-resistant schizophrenia

• For individuals whose illness has not adequately responded to clozapine at an optimised dose, confirm prior compliance and engagement before adding a second antipsychotic. Choose an augmenting drug that does not compound the common adverse effects of clozapine.

Comparison with other guidelines

• Unlike NICE, which makes no specific antipsychotic recommendation in first-episode psychosis, the RANZCP guidelines recommend atypical antipsychotics.
• RANZCP also explicitly suggests or permits the use of LAI agents in the first episode, a stance shared by the BAP guidelines.
• The duration of antipsychotic treatment in the first episode is not clearly specified by NICE. The CPA guidelines recommend at least 18 months, BAP suggests at least 2 years, and RANZCP recommends 2–5 years.
• Treatment for negative symptoms receives limited attention across guidelines. NICE recommends psychological approaches, while RANZCP tentatively suggests rTMS.
• Regarding clozapine-resistant schizophrenia, there is little significant detail or difference among guideline recommendations; all propose adding a second antipsychotic.

When treatment with the current antipsychotic medication seems suboptimal, either due to problematic adverse effects despite good symptom control or an inadequate therapeutic response, clinicians face several choices if clozapine is not pursued. These include increasing the dose, switching medications, adding an adjunctive medication, or monitoring. Unfortunately, the evidence base supporting these management options is limited.

Optimal dosage

While the recommended doses of SGAs are generally based on extensive clinical trials, the consensus on optimal dosages has evolved. For instance, although clinical practice initially moved towards lower doses of risperidone, the consensus for quetiapine has shifted towards higher doses, though RCT and other evidence does not consistently support this shift towards higher doses.

High dosage

The dose–response relationships for antipsychotics in treating schizophrenia are not well defined. A 2020 meta-analysis concluded that doses higher than standard doses were generally not more efficacious in acute schizophrenia. However, it suggested that for a few medications with clearly increasing dose curves (like olanzapine, lurasidone, ziprasidone), testing higher-than-licensed doses in clinical trials might be warranted. Findings from a network meta-analysis on lurasidone suggested 160mg/day might be the most effective and acceptable dose.

It's important to note that while therapeutic benefit often plateaus, the likelihood of inducing EPSEs is not similarly constrained; the frequency of EPS continues to increase at doses well beyond standard or even high doses.

Regarding specific trials, a study evaluating increasing lurasidone from 80mg/day to 160mg/day in early non-responsive schizophrenia showed significant symptom improvement compared to continuing 80mg/day. However, the clinical implications are uncertain due to the trial's limitations: a short duration (4 weeks) and no testing of the intermediate 120mg/day dose.

A 2018 Cochrane review found no good-quality evidence that increasing the antipsychotic dose differed from continuing the same dose for illness not responding initially. A similar meta-analysis in 2023 concluded that evidence for strategies like dose escalation or switching antipsychotic medication in early non-responsive schizophrenia was too limited for strong clinical recommendations.

Plasma level variations

Significant inter-individual variations exist in plasma drug levels. Genetic analysis can be helpful in identifying individuals who are ultrafast metabolisers of specific antipsychotics like aripiprazole, risperidone, and clozapine, which might explain lower-than-expected plasma levels despite higher doses.

Treatment options for schizophrenia that is poorly responsive to standard antipsychotic treatment

If clozapine is the indicated next step but is not used, options include switching or adding another non-clozapine antipsychotic. Significant delays in commencing clozapine treatment have been found not only in general practice but also specifically within early intervention in psychosis services. When considering findings suggesting delay or underuse of clozapine, it's important to remember that among patients diagnosed with treatment-resistant illness who haven't had a trial, some may have declined, some might still need persuasion, and for others, the clinician may judge another intervention more favourable due to factors like comorbidities, substance use, or adverse social circumstances.

Switching antipsychotics can be associated with illness destabilisation and the emergence of adverse effects related to stopping the original drug, starting the new one, or pharmacological differences. Minimising these issues often involves a gradual cross-tapering approach, which is usually recommended.

Recent evidence reinforces the position of specific agents after initial treatment failure. A systematic review found high-dose olanzapine superior to other commonly used FGAs and SGAs, including risperidone, for TRS. A network meta-analysis confirmed olanzapine as the second most effective antipsychotic (behind clozapine) for such illness.

Adding another antipsychotic (polypharmacy) remains a common strategy. A 2022 UK clinical audit found 14% of people on acute adult psychiatric wards were prescribed more than one antipsychotic, most commonly due to insufficient response to standard-dose monotherapy. While the theoretical rationale for combining drugs that primarily block D2 receptors is limited (with xanomeline and pimavanserin being exceptions), studies have examined various combinations. Systematic evidence is strongest for adding a second antipsychotic to clozapine. However, a meta-analysis of RCTs comparing augmentation with a second antipsychotic versus monotherapy found a lack of high-quality evidence for efficacy for a range of combinations. Antipsychotic combinations are associated with an increased adverse-effect burden and risk of high-dose prescribing, although at a population level, polypharmacy does not appear to increase hospitalisation rates for physical or specifically cardiovascular illness.

Most RCT evidence suggests that switching patients stable on polypharmacy back to monotherapy can often be done safely without symptom exacerbation.

When considering whether to continue the current regimen versus making changes, it's noted that staying with the current pharmacotherapy and focusing on non-pharmacological means may often do less harm than aimless switching and dosage increments.

When treatment fails

• If the dose of antipsychotic medication has been optimised, consider watchful waiting.
• Consider increasing the antipsychotic dose according to tolerability and plasma levels (little supporting evidence for most drugs).
• If this fails, consider switching to olanzapine or risperidone (if not already used).
• If this fails, use clozapine (supporting evidence very strong).
• If clozapine fails, use time-limited augmentation strategies (supporting evidence variable).

• Agitated states resulting from illicit substance misuse are addressed in Chapter 9.
• In addition to existing guidelines and reviews, a network meta-analysis focusing on RT within the emergency department setting has been published.

Oral/inhaled treatment

• The use of inhaled loxapine is now restricted in numerous countries due to the associated risk of bronchospasm.
• Dexmedetomidine, an α2 receptor agonist typically used in anaesthesia, has been formulated as a sublingual film and appears to be rapidly effective for managing acute agitation.

Parenteral treatment

• Research indicates that the combination of IM droperidol with IM midazolam proved more effective than the combination of IM haloperidol with IM lorazepam.
• More recent studies utilizing 5mg IM midazolam have demonstrated its rapid effectiveness.
• Ketamine, although widely used and potentially the most effective treatment for agitation in emergency departments, requires facilities for intubation due to risks like laryngospasm and the frequent need for intubation post-administration.

Rapid tranquillisation summary

• Oral treatment (Step 2): Inhaled loxapine is no longer listed as an option. Offer oral treatment if the patient is not already taking a regular oral or LAI antipsychotic (previously just oral or depot).
• Physical Monitoring: Following parenteral drug administration, all patients must be continuously observed ('in sight') for a minimum of 1 hour and until they are clearly ambulatory.

Guidelines for the use of flumazenil

• Adverse effects: Potential adverse effects include cardiac arrhythmia, specifically supraventricular tachycardia.

Real-world studies confirm that continued treatment with LAIs is associated with fewer relapses and hospital readmissions compared to oral antipsychotics.

A 2020 systematic review found LAI antipsychotics (specifically haloperidol and fluphenazine) were more effective than oral antipsychotics in maintenance treatment compared to placebo. A 2021 systematic review and meta-analysis encompassing various study designs (RCTs, observational cohort, pre–post studies) concluded that LAIs were associated with a reduced risk of hospitalisation or relapse across all designs examined. There are also indications from meta-analyses that some adverse effects might occur less frequently with LAIs compared to their oral equivalents.

While LAIs reduce relapse risk, they do not offer complete protection. Relapse in clinical practice is strongly associated with delayed or missed LAI doses. Studies indicate patients receiving fewer than the scheduled annual doses (e.g., 10 or fewer for monthly paliperidone) have a substantially higher risk of relapse. Consistently administered very long-acting injections might provide better protection against relapse.

LAI antipsychotic medication is recommended for all patients, particularly when preferred by the patient for convenience or when avoiding covert non-adherence is a clinical priority. LAIs ensure clinical awareness of adherence. Failure to adhere, signalled by missed appointments, allows prompt intervention. Using LAIs can help differentiate between non-adherence and true treatment resistance.

The relatively low usage of LAIs in some regions, like the USA, might partly stem from clinician reluctance rather than patient resistance, as studies show first-episode patients are often willing to accept this treatment form.

Advice on prescribing LAIs

• Test doses
  • Avoid LAIs in patients with a history of serious adverse effects like NMS due to their long half-life.
  • For LAI FGAs, a test dose (small amount of drug in oil) assesses sensitivity to EPS and the oil base.
  • For LAI SGAs, test doses may not be mandatory (lower EPS risk, aqueous base not known to be allergenic). However, consider a test dose if non-adherence to oral medication is suspected and the LAI represents the first guaranteed delivery of medication.
  • Prior treatment with the equivalent oral formulation to establish the optimally effective and tolerated dose is advised before starting an LAI, though not always essential from a pharmacokinetic standpoint for most SGAs (which often require loading doses like paliperidone and aripiprazole).
• Dosing and Interval
  • For LAI FGAs, evidence for dose-response effects is limited, and data on optimal dosing are scarce. Lower doses within the licensed range might be as effective as higher ones.
  • Administer LAIs at the longest possible licensed interval. There's no evidence that shortening the interval enhances efficacy. Less frequent injections are preferable due to potential injection site discomfort and pain; these reactions might be more common with oil-based LAI formulations.
  • While some patients report deterioration before their next injection, at steady state, trough plasma levels typically remain well above the therapeutic threshold.
• Dose Adjustment
  • Peak plasma levels, therapeutic effects, and steady-state concentrations are delayed with LAIs compared to oral forms. Dose increases should only follow careful assessment over at least a month, preferably longer, as plasma levels accumulate over weeks to months initially (steady state typically after 6–8 weeks). Increasing doses during this initial accumulation phase is illogical.
  • Ongoing monitoring of efficacy, adverse effects, and physical health impact is recommended, although the frequency of adverse effect assessment in clinical practice seems relatively low.
• Adding Oral Antipsychotic
  • Regular co-prescription of an oral antipsychotic with an LAI (once common with FGAs) might offer flexibility but carries uncertain long-term safety and tolerability. This practice may lead to an inadvertent high-dose prescription, increasing the adverse effect burden and physical health monitoring needs.

Differences between LAIs

A 2021 network meta-analysis of RCTs suggested that LAI formulations of paliperidone (3-month), aripiprazole, olanzapine, and paliperidone (1-month) demonstrated the largest effect sizes and greater certainty of evidence for both relapse prevention and acceptability.

LAI SGAs (aripiprazole, paliperidone, risperidone, olanzapine) generally show comparable efficacy but differ in their specific adverse effect profiles (e.g., weight gain, metabolic issues, EPS, hyperprolactinaemia). For instance, LAI paliperidone is linked to significant prolactin increases, while LAI olanzapine can cause notable weight gain and carries a risk of post-injection delirium/sedation syndrome.

Specific LAI Formulations and Characteristics:

• Aripiprazole (Abilify Maintena): 300–400mg monthly (buttock). Does not increase prolactin.
• Aripiprazole (Abilify Asimtufil): 720–960mg every 2 months (gluteal). Can be initiated after oral loading or continued from monthly injections.
• Aripiprazole (Aristada Initio): Single 675mg dose (deltoid or gluteal), not for repeat dosing. Given with 30mg oral aripiprazole. The first Aristada injection follows within 10 days.
• Aripiprazole (Aristada): 441mg, 662mg monthly; 882mg every 4–6 weeks; 1062mg every 2 months (deltoid† or gluteal). Can start with Aristada Initio + oral dose, or with 21 days oral overlap. (†Deltoid only for 441mg dose).
• Flupentixol decanoate (Depixol): 20mg test dose. 50mg/4 weeks to 400mg/week, every 2–4 weeks (buttock or thigh). Max licensed dose relatively high.
• Fluphenazine decanoate (Modecate): 12.5mg test dose. 12.5mg/2 weeks to 100mg/2 weeks, every 2–5 weeks (gluteal). High EPS risk.
• Haloperidol decanoate (Haldol): 25mg test dose (manufacturer guidance varies). 50–300mg every 4 weeks (gluteal). High EPS risk.
• Olanzapine pamoate (ZypAdhera): 150mg/4 weeks to 300mg/2 weeks, every 2–4 weeks (gluteal). Risk of post-injection syndrome.
• Paliperidone palmitate (Xeplion - monthly): 50–150mg monthly (deltoid or gluteal). Requires loading dose at initiation.
• Paliperidone palmitate (Trevicta - 3-monthly): 175–525mg every 3 months (deltoid or gluteal). Start only after ≥4 months on monthly LAI. Not for acutely agitated patients.
• Paliperidone palmitate (Byannli - 6-monthly): 700–1000mg every 6 months (gluteal). Start only after stabilization on monthly (≥4 months) or 3-monthly (≥1 cycle) LAI. Contraindicated in mild renal impairment (CrCl 50-80 mL/min).
• Pipothiazine palmitate (Piportil): 25mg test dose. 50–200mg every 4 weeks (gluteal). Lower relative EPS risk vs other FGAs.
• Risperidone microspheres (Risperdal Consta): 25–50mg every 2 weeks (deltoid or gluteal). Requires 2–3 weeks oral overlap due to delayed release.
• Risperidone (Perseris): 90–120mg monthly via subcutaneous injection in the abdomen.
• Risperidone (Okedi): 75–100mg every 28 days (deltoid or gluteal). Loading dose not required.
• Zuclopenthixol decanoate (Clopixol): 100mg test dose. 200mg/3 weeks to 600mg/week, every 2–4 weeks (buttock or thigh). High EPS risk.

• Aripiprazole (Abilify Maintena)
  • Time to peak plasma concentration varies by injection site: 4 days for deltoid injection, 5-7 days for gluteal injection.
  • Plasma half-life is approximately 27 days.
  • Time to steady state remains around 20 weeks.
• Aripiprazole 2-monthly injection (Abilify Maintena)
  • Time to peak plasma concentration: 28 days.
  • Plasma half-life: Approximately 29 days.
  • Time to steady state: Approximately 6 months.
• Aripiprazole lauroxil (Aristada in USA)
  • Time to peak plasma concentration: 44-50 days.
  • Plasma half-life: ~54-57 days.
  • Time to steady state: Approximately 4 months.
• Haloperidol decanoate (Haldol)
  • Time to peak plasma concentration: 3-9 days.
  • Plasma half-life: 21 days.
  • Time to steady state: ~14 weeks.
• Olanzapine pamoate (ZypAdhera)
  • Time to peak plasma concentration: 2-6 days.
  • Plasma half-life: 30 days.
  • Time to steady state: ~12 weeks.
• Paliperidone palmitate (6-monthly) (Byannli)
  • Time to peak plasma concentration: 29 days for the 700mg dose, 32 days for the 1000mg dose.
  • Plasma half-life: 148 days for the 700mg dose, 159 days for the 1000mg dose.
  • Time to steady state: Not known.
• Risperidone extended-release injectable suspension (Rykindo in USA)
  • Time to peak plasma concentration: 14 days for the 25mg dose, 17 days for the 50mg dose.
  • Plasma half-life: 3-6 days.
  • Time to steady state: Approximately 4 weeks.
• Risperidone in situ microimplants (ISM) (Okedi)
  • Shows two peaks in plasma concentration:
    • First peak: 1-2 days.
    • Second peak: 18-25 days.
  • Plasma half-life: 7-9 days.
  • Time to steady state: Approximately 4 weeks.
• Risperidone microspheres (Risperidal Consta)
  • Time to peak plasma concentration: Approximately 28 days.
  • Plasma half-life: 3-6 days.
  • Time to steady state: ~8 weeks.
• TV-46000 (risperidone SC) (Uzedy in USA)
  • Time to peak plasma concentration: 8-14 days.
  • Plasma half-life: 14-22 days.
  • Time to steady state: Approximately 2 months.
• General Notes on Pharmacokinetics
  • Attainment of steady state (SS) follows logarithmic characteristics; nearly 90% of SS levels are achieved in three half-lives. Time to steady state is independent of dose or dosing frequency. Loading doses can achieve therapeutic plasma levels sooner, but do not shorten the time to reach steady state.
  • Steady state concentration is not identical to the concentration needed for a therapeutic effect. For most depot medications, the concentrations reached during the dosing interval at steady state are typically somewhat higher than the minimum concentration required for a therapeutic response.

Regular Review

• Patients on long-term LAI antipsychotic treatment require essential follow-up, including at least an annual review by the responsible psychiatrist (ideally more often).

Assessment Components

• This review must systematically assess the medication's efficacy, tolerability, and safety.
• Assessment of adverse effects should specifically include:
  • Cardiovascular effects
  • Metabolic adverse effects
  • EPS, particularly parkinsonism, akathisia, and TD.

Dosage Considerations and Relapse Risk

• Reducing the dosage requires caution and close monitoring due to the increased risk of relapse and rehospitalisation associated with doses lower than standard, especially over the longer term.
• A 2022 naturalistic study involving a large nationwide cohort found that the risk of severe relapse (rehospitalisation) was lowest when patients continued on standard dose LAI treatment.
  • Exceptions noted were better outcomes associated with high-dose olanzapine LAI and relatively low-dose oral perphenazine.

Dose Reduction Process

• When reducing the dose:
  • Reduce by no more than one-third of the previous dose at any single time.
• Consider that relapse following the discontinuation of LAI formulations may be delayed compared to their oral counterparts or shorter-acting LAIs. This is likely due to their longer half-lives, resulting in longer exposure and prolonged dopamine receptor blockade after stopping.
• If a patient becomes symptomatic after a dose reduction, view this as valuable information for identifying the minimum effective dose required for that individual.
• Complex hyperbolic tapering regimens have been suggested and might offer some protection against relapse during dose reduction or discontinuation.

Patient Circumstances

• Before considering dose reduction, perform a risk-benefit analysis for the individual patient, taking into account:
  • Symptom status and duration of stability.
  • Severity, tolerability, distress, and disabling nature of current adverse effects.
  • Previous illness patterns (onset speed, relapse severity, risks).
  • Outcomes of any previous dose reduction attempts.
  • Current social circumstances and potential stressors.
  • Potential social consequences of relapse.
  • Patient's ability to self-monitor symptoms and seek help.

Aripiprazole 1-monthly

Aripiprazole long-acting injection (ALAI) is a useful alternative to other second-generation antipsychotic LAIs due to its lack of prolactin-related and significant metabolic adverse effects. It has demonstrated good efficacy in both acute and longer-term treatment of schizophrenia. In the USA, it is also approved for maintenance monotherapy in bipolar I disorder, though this use is off-label in the UK and some other regions.

• Initiation:
  • Before starting ALAI, oral aripiprazole (10–20mg/day) should generally be given for 14 days to confirm tolerability and response. This oral period is also crucial for the loading process.
  • If switching from a different oral antipsychotic, ensure aripiprazole was effective and tolerated previously. The current oral antipsychotic should be continued for the first 14 days after the initial ALAI dose.
  • Two initiation regimens are available:
    1. One-injection start: Administer one 400mg ALAI injection. Continue oral aripiprazole (10–20mg/day) for 14 consecutive days (totaling 28 days of oral coverage from the pre-initiation phase if applicable, or 14 days post-injection if starting directly). Without this 14-day oral overlap post-injection, plasma levels might be insufficient.
    2. Two-injection start: Administer two separate 400mg ALAI injections on the same day at different injection sites (e.g., separate gluteal muscles, separate deltoid muscles, or one gluteal and one deltoid). Give a single 20mg dose of oral aripiprazole concurrently. Oral therapy should not continue after this single dose. The necessity of this single oral dose is potentially questionable given the large depot dose.
  • One month (defined by the manufacturer seemingly as every 28 days) after initiation, begin the monthly 400mg regimen. A 400mg monthly dose is approximately equivalent to 15–20mg of daily oral aripiprazole.
• Pharmacokinetics:
  • After the one-injection start with oral overlap, peak plasma levels occur around 7 days post-injection, with trough levels at 4 weeks.
  • After the two-injection start, peak plasma concentration is seen at 5–7 days (gluteal injection) or 4 days (deltoid injection).
  • Steady-state plasma levels are typically achieved after the fourth injection for both administration sites.
• Dosing and Tolerability:
  • The standard maintenance dose is 400mg monthly.
  • A lower dose of 300mg monthly can be used for patients who do not tolerate 400mg or who are known poor metabolisers via CYP2D6.
  • A 200mg monthly dose is reserved for patients taking specific enzyme-inhibiting drugs.
  • Most common adverse events include increased weight, akathisia, insomnia, and injection site pain.
• Managing Missed Doses:
  • Specific guidance is available for managing delayed or missed doses, depending on whether it's an early dose (2nd or 3rd) or a later dose (4th onwards) and the duration since the last injection. Strategies may involve administering the dose as soon as possible or re-initiating with oral supplementation or the two-injection start method if the delay is significant (e.g., >5 weeks for early doses, >6 weeks for later doses).
• Switching:
  • When switching from oral antipsychotics, cross-taper onto oral aripiprazole for about 2 weeks before initiating ALAI using either the one-injection or two-injection start method as described above. If prior response/tolerability is known, the oral aripiprazole run-in might not be strictly needed, but achieving effective levels relies on the oral supplement (one-injection start) or assumes therapeutic levels of the prior antipsychotic or steady-state oral aripiprazole (two-injection start). If starting ALAI without prior oral aripiprazole (e.g., due to refusal), the two-injection start (800mg total) is preferred as it's likely to provide therapeutic concentrations.
  • When switching from most depot antipsychotics (excluding Risperidone Consta), start oral aripiprazole on the day the last depot was due, continue for 2 weeks, then initiate ALAI.
  • When switching from Risperidone Consta, start oral aripiprazole 4–5 weeks after the last risperidone injection, continue for 2 weeks, then initiate ALAI.

Aripiprazole 2-monthly

A 2-monthly formulation (Aripiprazole 2-Month Ready-to-Use 960mg, Ari 2MRTU) is available for the maintenance treatment of schizophrenia (and in the USA, for maintenance monotherapy of bipolar I disorder).

• Formulations and Administration:
  • Available as 720mg and 960mg prefilled syringes.
  • Must be administered into the gluteal muscle only.
  • The 960mg dose is equivalent to 10–20mg daily oral aripiprazole.
• Initiation:
  • From oral antipsychotics: Establish tolerability with oral aripiprazole first.
    • One-injection start: Give one 960mg injection plus 10–20mg oral aripiprazole daily for 14 consecutive days.
    • Two-injection start: Give one 960mg injection and one 400mg ALAI injection at two different sites, plus one 20mg dose of oral aripiprazole.
  • From 400mg ALAI (1-monthly): Initiate the 960mg 2-monthly dose no sooner than 26 days after the last 400mg ALAI injection.
• Maintenance:
  • The maintenance dose (960mg or 720mg) should be given every 56 days (manufacturer's definition of '2-monthly').
  • Injections can be administered up to 2 weeks before or 2 weeks after the scheduled date.
• Dose Adjustments and Missed Doses:
  • Reduce the dose to 720mg every 2 months in case of adverse reactions.
  • The 720mg dose is also appropriate for patients on concomitant CYP2D6 or CYP3A4 inhibitors or known CYP2D6 poor metabolisers.
  • Guidance exists for managing missed doses:
    • If >8 weeks and <14 weeks since the last injection: Give the usual dose as soon as possible.
    • If >14 weeks since the last injection: Re-initiate treatment by giving the usual maintenance dose plus 14 days of oral aripiprazole, or by giving an augmented injection regimen (e.g., 960mg dose requires 960mg + 400mg injections + single 20mg oral dose). Resume the 2-monthly schedule thereafter.
• Tolerability:
  • Ari 2MRTU 960mg is generally well tolerated, with safety, efficacy, and pharmacokinetic profiles similar to the 1-monthly 400mg ALAI.

Other LAI Aripiprazole Brands (Aripiprazole Lauroxil)

Two other long-acting formulations, Aristada Initio and Aristada (aripiprazole lauroxil), are approved by the FDA in the USA for treating schizophrenia. Aripiprazole lauroxil is a pro-drug of aripiprazole.

• Aristada Initio:
  • Used for initiation only.
  • Administered as a single 675mg IM injection into the gluteal muscle.
  • Typically given alongside a single 30mg dose of oral aripiprazole.
  • This allows initiation of Aristada maintenance doses on the same day or up to 10 days later.
• Aristada (Maintenance Dosing):
  • Administered at 1-monthly, 6-weekly, or 2-monthly intervals.
  • Available strengths: 441mg, 662mg, 882mg, 1064mg (delivering approximately 300mg, 450mg, 600mg, and 724mg of aripiprazole, respectively).
  • Injection site depends on dose:
    • 441mg: Deltoid or gluteal (monthly).
    • 662mg, 882mg: Gluteal only (monthly).
    • 882mg (alternative): Gluteal only (every 6 weeks).
    • 1064mg: Gluteal only (every 2 months).
  • Dose equivalence examples:
    • 10mg/day oral ≈ 441mg monthly Aristada.
    • 15mg/day oral ≈ 662mg monthly, or 882mg every 6 weeks, or 1064mg every 2 months Aristada.
    • ≥20mg/day oral ≈ 882mg monthly Aristada.
• Initiation Options for Aristada Maintenance:
  1. 1-Day Initiation: Give Aristada Initio (675mg IM gluteal) + single 30mg oral aripiprazole dose. Start the chosen Aristada maintenance dose on the same day or within 10 days. (Avoid giving Initio and Aristada in the same muscle).
  2. Oral Overlap: Give the first Aristada maintenance dose (IM) and continue concomitant oral aripiprazole for 21 days.
• Tolerability:
  • The most commonly reported adverse reaction is akathisia.
  • The 1-day initiation regimen (using Aristada Initio) has shown a safety/tolerability profile comparable to paliperidone palmitate 1-monthly, with most adverse events (injection-site pain, akathisia, increased weight) occurring early in treatment.
• Comparison (Aristada 1064mg vs. Ari 2MRTU 960mg):
  • Both provide therapeutic plasma levels over a 2-month interval.
  • Key differences:
    • Dosing Equivalence: Aristada 1064mg corresponds to ~15mg/day oral aripiprazole; Ari 2MRTU 960mg corresponds to ~10–20mg/day oral aripiprazole.
    • Indications: Both for schizophrenia; Ari 2MRTU also approved for bipolar I maintenance in the USA.

• Olanzapine pamoate is a very poorly water-soluble salt ester of olanzapine.
• When injected deep into the gluteal muscle, the aqueous suspension provides both prompt and sustained release.
• The manufacturer recommends that patients first receive oral olanzapine to evaluate response and tolerability.

Switching

• When switching from a different LAI, oral or LAI olanzapine can commence on the day the previous LAI was scheduled.
• When switching from Risperidone Consta, it is suggested to start olanzapine 2 weeks after the last Consta injection was due (which equates to 4 weeks after the final Consta injection). Peak plasma levels of risperidone typically occur 4–5 weeks following the last injection.

Stopping

• When discontinuing treatment, clinicians should account for the gradual release of olanzapine from the pamoate salt.
• Various methods are available to ensure a linear decrease in drug activity.
• Olanzapine might remain detectable in the bloodstream for as long as 8 months after the final dose.

Post-injection delirium sedation syndrome (PDSS)

• The precise mechanism is unclear, but PDSS is believed to happen when the olanzapine pamoate salt is accidentally exposed to a large volume of blood or plasma (e.g., through intravenous injection or blood vessel injury).
• This exposure can lead to faster dissolution of the salt and the release of a substantial amount of olanzapine into circulation.
• Olanzapine plasma levels can exceed 800mcg/L, resulting in confusion, delirium, and somnolence.
• Treatment involves supportive care, and outcomes are consistently good.
• The mean time for reactions to occur is 30 minutes, and they typically resolve completely within 72 hours.
• Shortening the observation period to 2 hours is practiced in Australia and New Zealand, among other countries.
• Shorter monitoring durations were also utilized during the COVID-19 pandemic.
• PDSS can happen at any time and lacks clear predictive risk factors. Prior safe use in a patient does not indicate a low risk of future PDSS.
• The risk might be lower for patients receiving injections at 1-monthly intervals, likely due to receiving fewer injections overall.
• The SPC guidance applies in the EU and the UK.
• No patient or medical factor has been identified that definitively predicts PDSS. However, individuals experiencing the syndrome might be somewhat more likely to have had a previous injection site-related adverse effect. Male gender and higher doses have also been proposed as potential risk factors.

Paliperidone (9-hydroxyrisperidone) is the active metabolite of risperidone.