Antipsychotic combination/augmentation

Time for therapeutic effect

It is essential that there has been a trial of adequate duration and dose to establish effect, partial response or non-response:

• No response to medication after four weeks despite dose optimisation, a change in antipsychotic should be considered
• Where there is partial response, this should be re-assessed after eight weeks unless there are significant adverse effects¹.

Some individuals will respond to treatment after a number of months². BAP recommends that for an adequate trial, clozapine monotherapy should be prescribed for 3-6 months³.

Dosing and pharmacodynamics

All antipsychotics vary in their affinity for D2 receptors (see receptor profiles).

To effectively treat the positive symptoms of schizophrenia, antipsychotics need to block at least 60% of D2 receptors (clozapine being the exception).

Effective D2 blockade is achieved at different dose levels and may only be achieved after the concentration is sufficient to block other receptors. When an antipsychotic has stronger affinity for a particular receptor system than for the dopaminergic system, a side effect associated with the blockade of this receptor is likely to occur within the dose range required for antipsychotic efficacy e.g. quetiapine has stronger affinity for histaminergic and alpha-adrenergic receptors than dopaminergic, therefore sedation and postural hypotension are likely to occur within the therapeutic dose range (see receptor affinity).

There are subsets of patients who both tolerate and require high levels of D2 antagonism for symptom control and respond to high doses that achieve greater than the traditional degree of D2 receptor occupancy⁴.

Changing antipsychotic monotherapy

Clozapine should always be considered in treatment resistant schizophrenia where other antipsychotics have failed to elicit an adequate response or caused intolerable adverse effects.

Where clozapine is not a viable option, an antipsychotic with a different receptor profile to those previously tried should be considered prior to combining antipsychotics e.g. switching to a first generation antipsychotic where only second generation antipsychotics have been prescribed previously.

Mood stabilisers and/or antidepressants should be considered especially where a mood disturbance is thought to contribute to symptoms.

Where there is not an obvious affective component, a mood stabiliser may also be worth considering in psychosis that has not responded to conventional antipsychotics.

Glutamatergic neurotransmission is altered in schizophrenia, therefore lamotrigine with a mechanism of action that inhibits excessive glutamate release may have a potential role as antipsychotic augmentation^5,6.

SIGN recommends lamotrigine augmentation of clozapine for individuals whose symptoms have had an insufficient response to clozapine¹.

There is also some evidence for the effectiveness of lithium as an add-on treatment with antipsychotics for schizophrenia, however a recent Cochrane review indicated that these were low quality studies⁷.

The evidence-base for antipsychotic augmentation is poor and not robust enough to allow recommendations for combinations to be made.

However combinations may be useful in some clinical situations and the choice of augmenting antipsychotic should be based on complementary receptor profiles in terms of optimising therapeutic effect and minimising adverse effects.

The following situations can be considered as appropriate indications for the use of combination antipsychotics:

• Augmentation of clozapine e.g. where clozapine has produced a partial response
• Clozapine is not a viable treatment option e.g. clozapine not tolerated or individual not willing to accept clozapine
• Switching from one antipsychotic to another e.g. temporary cross-titration
• During an acute exacerbation of illness e.g. used as a temporary measure
• Managing adverse effects e.g. hyperprolactinaemia or weight gain

The use of more than two antipsychotics should prompt an immediate review of medication.

Avoid pharmacodynamic redundancy

Using two drugs with the same or overlapping mechanism of action e.g. two potent D2 blockers, where the addition of one drug to another is unlikely to give additional clinical benefit but will increase the risk of adverse effects.

Consider pharmacodynamic interactions

Using two drugs with opposing mechanism of action e.g. the use of aripiprazole (a partial D2 agonist) with a potent D2 blocker. Aripiprazole will displace full D2 antagonists and potentially lead to a worsening of positive symptoms.

Consider pharmacokinetic interactions

Where one drug increases the metabolism of another e.g. carbamazepine induces metabolism of certain antipsychotics and reduces their plasma levels.

There are randomised controlled trials for augmenting clozapine; however a Cochrane review suggested that the results were limited and evidence is of low or very low quality⁹.

Augmentation strategies with clozapine should only be considered after clozapine treatment has been administered for an adequate period of at least 3 months³.

It may be appropriate to consider the use of therapeutic drug monitoring of clozapine when optimising the dose and prior to augmentation (Clozapine TDM guide).

When choosing the augmenting antipsychotic, consideration should be given to antipsychotics with a complementary receptor profile to clozapine, and a side effect profile that minimises adverse effects such as sedation, weight gain and metabolic effects.

An adequate trial of clozapine augmentation with another antipsychotic should be at least 10 weeks in duration^1,3.

Consideration may be given to using a second antipsychotic in order to manage the adverse effects of the original antipsychotic. For example;

• the addition of aripiprazole to individuals treated with clozapine to minimise side effects such as sedation, weight gain and other metabolic parameters¹⁰
• low dose aripiprazole* to manage symptomatic hyperprolactinaemia^11,12

*Aripiprazole (as a partial agonist) at relatively low doses (~10mg) can achieve >80% D2 occupancy and will displace full D2 antagonists and therefore may lead to a worsening of positive symptoms. The optimum dose of aripiprazole for managing symptoms of hyperprolactinaemia is approximately 5mg daily (range 3-6mg)^11,12.  There is no rationale for using higher doses as these may have a detrimental impact on mental state.

Good record-keeping and documentation is fundamental to all prescribing practices. When using antipsychotic augmentation strategies, it is essential to RECoRD:

• Rationale for treatment
• Evidence-base for combination where appropriate
• Consent - the patient and/or carer’s consent (and/or compliance with statutory treatment plans). Include the key elements of the discussion with the patient and/or carer regarding risks/benefits of treatment and alternative treatments where appropriate
• Review- the process and timescale for ongoing review of treatment with consideration to using symptom and side effect rating scales to objectively assess response and adverse effect burden
• Document all of the above in the patient’s clinical notes

+++ - high affinity; ++ - moderate affinity; + - low affinity; Ø - very low affinity;

? - unknown; PAg - partial agonist with very high affinity; Antag – antagonist

*olanzapine & clozapine have D2 limbic selectivity

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