Combining amisulpride with aripiprazole

Amisulpride and aripiprazole are both relatively selective for dopamine D₂/D₃ receptors and are not sedative. Amisulpride is licensed for schizophrenia, including patients with predominantly negative symptoms at lower doses (Krause Reference Krause, Zhu and Huhn2018). Aripiprazole does not share this advantage, which has been attributed to presynaptic D₃ receptor antagonism (Frank Reference Frank, Kiss and Keserű2018), although other receptor mechanisms have also been implicated. Amisulpride has greater efficacy than aripiprazole in reducing positive symptoms of schizophrenia but also greater occurrence of QT prolongation and diminished libido (Huhn Reference Huhn, Nikolakopoulou and Schneider-Thoma2019; Johnsen Reference Johnsen, Kroken and Løberg2020). Because of their different side-effects, it may be desirable to taper between one drug and the other, thus balancing the benefits of receptor occupancy (in terms of efficacy) against the side-effects.

Flexible occupancy by combining a full antagonist (amisulpride) and a partial agonist (aripiprazole)

The maximum degree of antagonist occupancy that can be achieved by aripiprazole is 75%, assuming intrinsic activity of 25% (see Cookson Reference Cookson, Pimm and Brentnall2023c). This means that by combining the two drugs in varying proportions at high doses, the level of antagonistic occupancy can be manipulated to anywhere between 73% (aripiprazole 30 mg/day alone) and 91% (amisulpride 1200 mg/day); at lower doses it is between 68% (aripiprazole 10 mg/day alone) and 80% (amisulpride 600 mg/day).

Potential worsening of psychosis after addition or switch

Eight reports reviewed by Takeuchi and Remington (Takeuchi Reference Takeuchi and Remington2013) described patients whose psychosis worsened or agitation increased after the addition of aripiprazole to another antipsychotic or switching to aripiprazole. Fourteen reports described worsening after a switch to aripiprazole. In most patients the doses of antipsychotics had exceeded recommended guidelines. A meta-analysis of randomised trials of such changes reported an excess of early discontinuation owing to lack of efficacy after switching but no increase in relapses after addition of aripiprazole (Takeuchi Reference Takeuchi, Fathi and Thiyanavadivel2018).

Worsening is sometimes (Takeuchi Reference Takeuchi and Remington2013) but not often seen as a problem in combination with clozapine (Fleischhacker Reference Fleischhacker, Heikkinen and Olie2010). D₂/D₃ receptor occupancy in acute treatment with clozapine is less than 70% (Farde Reference Farde, Nordstrom and Wiesel1992). Hence, any displacement by aripiprazole will increase blockade of dopamine, although adding some agonistic activity.

Psychosis worsened when adding aripiprazole to haloperidol

A 24-year-old female graduate with a 5-year history of schizophrenia was on haloperidol 20 mg daily and showed only slight improvement (Grover Reference Grover, Sharan and Gupta2006). Addition of aripiprazole led to worsened symptoms in the following weeks. Her condition improved when aripiprazole was discontinued.

The striking change in occupancy when aripiprazole was combined is that antagonistic occupancy was reduced from 94% to 83% while agonistic occupancy increased from at the most 6% to 14% (Table 1). This outcome was clear to recognise because the original dose of antipsychotic was such as to occupy a high proportion of receptors, leaving few to be occupied by dopamine.

TABLE 1 Adding 20 mg aripiprazole to 20 mg haloperidol daily

DssOcc50, the dose that produces 50% occupancy at steady state blood levels. Aripiprazole occupancy consists of 75% antagonism, as shown in parenthesis, and 25% agonism.

Adding aripiprazole to risperidone to reduce hyperprolactinaemia

Antipsychotics raise plasma prolactin and lower testosterone variably; the largest rises in prolactin are caused by amisulpride, risperidone and paliperidone; olanzapine causes only small increases (Huhn Reference Huhn, Nikolakopoulou and Schneider-Thoma2019). However, aripiprazole lowers plasma prolactin levels in a dose-dependent manner (Tasaki Reference Tasaki, Yasui-Furukori and Yokoyama2021). Thus, the intrinsic agonist activity of aripiprazole alone is more than sufficient to compensate for its blockade of endogenous dopamine in the pituitary (Box 1, Box 2).

BOX 2 Equations to determine the likely occupancy of D₂/D₃ dopamine receptors before and during addition of aripiprazole

DssOcc50(drug 1) is the dose of drug 1 producing 50% occupancy at steady state blood levels.

The values for DssOcc50 for each drug were derived from positron emission tomography studies

$$\% \;{\rm occupancy\;by\;drug\;}1 = {\rm \;}\displaystyle{{100\;[ {{\rm Dose\;of\;drug\;}1} ] } \over {[ {{\rm Dose\;of\;drug\;}1} ] + {\rm DssOcc}50( {{\rm drug}1} ) \left({1 + \displaystyle{{[ {{\rm Dose\;of\;drug\;}2} ] } \over {{\rm DssOcc}50( {{\rm drug}2} ) }}} \right)}}$$

$$\% \;{\rm occupancy\;by\;drug\;}2 = {\rm \;}\displaystyle{{100\;[ {{\rm Dose\;of\;drug\;}2} ] } \over {[ {{\rm Dose\;of\;drug\;}2} ] + {\rm DssOcc}50( {{\rm drug}2} ) \left({1 + \displaystyle{{[ {{\rm Dose\;of\;drug\;}1} ] } \over {{\rm DssOcc}50( {{\rm drug}1} ) }}} \right)}}$$

A randomised controlled trial of 30 people with schizophrenia found that addition of aripiprazole to risperidone normalised prolactin levels in 46% and improved erectile dysfunction in 5 out of 6 affected men (Raghuthaman Reference Raghuthaman, Venkateswaran and Krishnadas2015). A typical 45-year-old male was on 6 mg daily of risperidone and had been stable for more than 12 weeks. The patient developed erectile dysfunction; his plasma prolactin concentration was 2000 μIU/mL (normal <324). Aripiprazole 10 mg daily was added to his medication. Within 8 weeks, the prolactin concentration was within the normal range, his erectile function had improved; his mental state remained stable and he reported no other side-effects.

Risperidone 6 mg/day would normally occupy and antagonise 83% of D₂/D₃ receptors in the brain: more than enough to treat a relapse (Table 2).

TABLE 2 Predicted striatal dopamine D₂/D₃ receptor occupancy and antagonistic activity by risperidone (drug 1) and aripiprazole (drug 2) alone and in combination in the doses stated

DssOcc50, the dose that produces 50% occupancy at steady state blood levels. Aripiprazole occupancy consists of 75% antagonism, as shown in parenthesis, and 25% agonism.

Aripiprazole 10 mg would normally occupy 91% of D₂/D₃ receptors. As a partial agonist with 25% intrinsic activity, this would correspond to an antagonist occupancy of 68%.

In the combination, risperidone occupied 31% of D₂/D₃ receptors and aripiprazole occupied 63%. As a partial agonist with 25% intrinsic activity, this would correspond to an antagonist occupancy of 47% by aripiprazole in the combination.

The resulting total antagonist occupancy was 78% (31 + 47): still enough to prevent relapse despite the intrinsic activity of aripiprazole.

We have now to consider the interaction at the lactotroph cells of the anterior pituitary, where expression levels for D₂ are 100-fold higher than for D₃. Plasma prolactin rises above the normal range when D₂ antagonist occupancy in the pituitary overcomes the inhibitory effect of dopamine on prolactin secretion. We can use plasma concentrations of the drug to calculate pituitary D₂ receptor occupancy. As the great majority of the risperidone active moiety in plasma is its 9-hydroxy metabolite paliperidone, this dominates in raising prolactin levels (Knegtering Reference Knegtering, Baselmans and Castelein2005). For paliperidone alone, calculating free drug by accounting for protein binding (77%) gives 21.2 nM which, with a dissociation equilibrium constant K_d of 2.8 nM (Richelson Reference Richelson and Souder2000), indicates 88.3% occupancy.

The corresponding values for the parent compound risperidone are levels of 4.87 nM/L and a K_d of 3.77 nM. Table 3 shows the calculated occupancies. The paliperidone moiety alone would cause 88.3% occupancy, and the combined occupancy is 89.9%, substantiating the findings of Knegtering et al (Reference Knegtering, Baselmans and Castelein2005). Note that the pituitary D₂ receptor occupancy on risperidone 6 mg/day (89.9%) exceeds the calculated occupancy in the brain (83%).

TABLE 3 Predicted pituitary dopamine D₂ receptor occupancy on risperidone 6 mg/day by the risperidone moieties (drug 1 risperidone and drug 2 paliperidone, alone and in combination)

K_d, dissociation equilibrium constant.

For aripiprazole, the equivalent calculation – 180 ng/ml and 0.64% unbound (Hirata Reference Hirata, Ikeda and Watanabe2021) – yields 2.57 nM free drug from which, with a K_d of 0.34 nM (Burris Reference Burris, Molski and Xu2002), an occupancy of 88.3% is again calculated.

Applying the equation in Box 2 but substituting the K_d for the DssOcc50 (the dose producing 50% occupancy at steady state blood levels) and the drug concentration for the dose gives a combined occupancy with a paliperidone component of 46.5% and aripiprazole component of 46.9% (Table 4). Note that pituitary D₂ antagonistic occupancy has fallen from 89.9% to 81.7%. This contribution of D₂ partial agonism is presumably enough to overcome the antagonist block of the inhibitory effect of endogenous dopamine on prolactin secretion. (This calculation was simplified by ignoring the lesser contributions of risperidone parent compound and aripiprazole metabolites.)

TABLE 4 Predicted pituitary dopamine D₂ receptor occupancy and antagonistic activity by paliperidone moiety (drug 1) and aripiprazole (drug 2) alone and in combination in the doses stated

K_d, dissociation equilibrium constant. Aripiprazole occupancy consists of 75% antagonism, as shown in parenthesis, and 25% agonism.

It seems likely that the intrinsic activity of aripiprazole may be higher at lactotroph D₂ receptors than within the brain; studies of the functional effects of aripiprazole on lactotrophs in vitro indicate maximum activity of up to 70% that of dopamine (Kucka Reference Kucka, Tomić and Bjelobaba2015), well above the 25% reported for central D₂-like receptors.

There are many uncertainties in these calculations associated with extrapolation from experimental data and model systems. Calculated K_d values vary and, for example, the affinity of aripiprazole at the lactotroph D₂ sites may be higher than is generally quoted for brain tissue, which would result in a larger aripiprazole occupancy. Protein binding of drugs varies with physical health.

In summary, the beneficial effect of aripiprazole on prolactin in people on risperidone arises from a lowering in risperidone's antagonistic occupancy combined with the partial agonistic effect of aripiprazole.

Although the effectiveness of this intervention has been confirmed in a narrative review (Besag Reference Besag, Vasey and Salim2021), an alternative strategy might have been a switch to a different antipsychotic with a lower propensity to raise prolactin.

Regarding dose, a meta-analysis found doses of only 5 mg aripiprazole daily could be effective in reducing prolactin levels raised by risperidone or haloperidol (Li Reference Li, Tang and Wang2013). Further, Chen et al (Reference Chen, Huang and Ree2010) found aripiprazole less effective in lowering prolactin in people on amisulpride than in those on risperidone.

Jen et al (Reference Jen, Hwang and Chan2020) observed prolactin levels during a switch from other antipsychotics to aripiprazole in people with schizophrenia. Those whose prolactin levels became abnormally low during the switch were more likely to experience a worsening of psychosis. They interpret this as meaning that lowering of prolactin represented supersensitivity of dopamine receptors in the pituitary through upregulation during prolonged exposure. An alternative explanation is that lower prolactin indicates greater displacement of the previous antipsychotic by aripiprazole and therefore less antagonist occupancy to prevent relapse.

Adding aripiprazole to olanzapine for metabolic side-effects

For a review of the management of weight gain developing with antipsychotics, see Cooper et al (Reference Cooper, Reynolds and Barnes2016).

The mechanism of weight gain with olanzapine is likely to involve blockade primarily of 5-HT_2C receptors, although antagonism at other receptors, including histamine H1 and D₂/D₃, may also be involved in antipsychotic-induced weight gain (Reynolds Reference Reynolds and McGowan2017). Addition of aripiprazole would have minimal effect on H₁ receptors, but its partial agonism at 5-HT_1A sites may be protective in reducing the orexigenic effects of olanzapine (Snigdha Reference Snigdha, Thumbi and Reynolds2008). The addition of aripiprazole to clozapine, which also blocks histamine H₁ and 5-HT_2C (similarly to olanzapine) led to a mean weight loss of 2 kg over 16 weeks compared with adding placebo, according to meta-analysis by Choi (Reference Choi2015).

A 50-year-old man with schizophrenia was maintained on olanzapine 20 mg daily for over a year and had a body mass index (BMI) of 32. Aripiprazole was added (15 mg daily). After 4 weeks he had lost 2 kg in weight and no change in mental state was noted (Henderson Reference Henderson, Fan and Copeland2009).

Olanzapine 20 mg daily would be expected to occupy and antagonise approximately 83% of D₂/D₃ receptors: more than enough to treat a relapse (Table 5).

TABLE 5 Predicted striatal dopamine D₂/D₃ receptor occupancy and antagonistic activity by olanzapine (drug 1) and aripiprazole (drug 2) alone and in combination in the doses stated

DssOcc50, the dose that produces 50% occupancy at steady state blood levels. Aripiprazole occupancy consists of 75% antagonism, as shown in parenthesis, and 25% agonism.

Aripiprazole 15 mg would typically occupy 94% of D₂/D₃ receptors. As a partial agonist with 25% intrinsic activity this would correspond to antagonist occupancy of 70%.

In the combination, olanzapine occupied 23% of D₂/D₃ receptors and aripiprazole occupied 72%. As a partial agonist with 25% intrinsic activity, this would correspond to antagonist occupancy of 54% by aripiprazole in the combination. The agonistic occupancy is 18%.

The resulting total antagonist occupancy was 77% (23 + 54), sufficient to counteract the roughly 18% agonistic occupancy by aripiprazole for the purpose of controlling psychotic symptoms. A longer follow-up than 4 weeks would be important to confirm that weight loss and stability of symptoms were maintained.

Controlling a relapse with severe agitation during treatment with aripiprazole

In a psychiatric intensive care setting, it is common to see a patient admitted with a psychotic episode in whom aripiprazole has been used in the community but who is now severely agitated.

A young man had been taking aripiprazole 30 mg daily but developed a psychotic episode with severe agitation and manic symptoms and required tranquillisation. Aripiprazole was discontinued and haloperidol 20 mg daily was commenced, an electrocardiogram (ECG) having been normal. Promethazine and lorazepam were also given, in keeping with guidelines (Cookson Reference Cookson2018).

Haloperidol 20 mg daily would normally occupy and antagonise 94% of D₂/D₃ receptors, well above the level needed to treat most relapses. However, occupancy data from positron emission tomography (PET) scans are not available for people with severe agitation (Table 6).

TABLE 6 Predicted striatal dopamine D₂/D₃ receptor occupancy and antagonistic activity by haloperidol (drug 1) and aripiprazole (drug 2) alone and in combination in the doses stated

DssOcc50, the dose that produces 50% occupancy at steady state blood levels. Aripiprazole occupancy consists of 75% antagonism, as shown in parenthesis, and 25% agonism.

Aripiprazole 30 mg would normally occupy 97% of D₂/D₃ receptors. As a partial agonist with 25% intrinsic activity, this would correspond to antagonist occupancy of 73%. This is not always sufficient to prevent a relapse.

In the combination, haloperidol occupied 33% of D₂/D₃ receptors and aripiprazole occupied 65%. As a partial agonist with 25% intrinsic activity, this would correspond to antagonist occupancy of 48% by aripiprazole in the combination.

The resulting total antagonist occupancy was 81% (33 + 48); although usually enough to treat acute relapses of schizophrenia, this, we are assuming, was not sufficient to treat the psychosis in the presence of 17% agonistic occupancy by aripiprazole.

The man remained extremely agitated and refused oral medication.

Having discontinued aripiprazole 30 mg/day, even after 6 days, with an elimination half-life of 3 days, aripiprazole levels would still be equivalent to those resulting from a steady dose of 7.5 mg a day, sufficient alone (with a DssOcc50 of 1 mg/day) to cause D₂/D₃ receptor occupancy of 88%.

In summary, the psychotic manic agitation would be improving more slowly than expected with haloperidol.

To achieve greater antagonistic occupancy would require exceeding the upper limit of dose for haloperidol recommended in the British National Formulary, with concerns about potential ECG changes. An alternative approach would be the use of intramuscular zuclopenthixol acetate (Patel Reference Patel, Sethi and Barnes2018). Using the DssOcc50 of less than 12.5 mg, the recommended initial dose of 150 mg would produce occupancy of 92% alone; a cumulative dose of 450 mg would produce 97% occupancy alone.