The More, the Merrier…? Antipsychotic Polypharmacy Treatment Strategies in Schizophrenia From a Pharmacology Perspective

Figure 1. Antipsychotic polypharmacy (APP)—broad literature background impressions.

Figure 2. Stepwise transition to APP, based on NICE, UK, Clinical Guidelines (5).

Figure 3. Commonly given pharmacodynamically (PD)-based reasons to initiate APP.

Figure 4. Target and associated AE profiles of HAL, OLA, RIS, ARI, and CAR. Colored lines and dots represent drug profiles based on the 8 different targets depicted at the edges of the cobweb; affinity is highest at the center, lowest at the edges (0.1–10,000 nM log scale). Dot line-enclosed shaded areas in the center represent unbound plasma levels of the compounds at efficacious therapeutic dosing. Circles and ovals depict targets likely to be affected at these levels, with colors indicating desired (yellow), accessory beneficial (light blue), and unwanted effects (red; + text below graphs). Red ovals in ARI and CAR graphs pinpoint D2 and D3 affinities. EPS, Extrapyramidal side effects; PRL, prolactin (rise). The drug cobweb profiles in this figure and Figures 5, 6 were compiled from data in public web databases and complementary literature, including drug SPC's; viz. human (cloned or native tissue) receptor affinities (22–24); therapeutic steady-state exposures1 (25); free fraction of drug plasma concentrations (26). Therapeutic steady-state exposure areas shown were obtained by converting ng/mL (25) to nM, and multiplying by the free fraction in plasma (26) for the corresponding drug.

Figure 5. Some potentially useful APP target combinations based on FGA, SGA, and TGA. Shown are target profiles of APP combination examples based on CLZ, OLA, QUE, ARI, and CAR, displayed in a cobweb design. The colored lines joining the dots represent the target profile of the agent with corresponding color coding; e.g., blue is CLZ, and green is CAR. The dot line-enclosed shaded areas represent unbound plasma concentrations of the compounds at therapeutic dosing. For example, in the OLA + CAR case, the yellow and pink areas show unbound OLA and CAR plasma concentrations, respectively. For further explanations, see legend to Figure 4.

Figure 6. Some theoretically suboptimal, less preferable—or even futile—APP target combination examples based on FGA, SGA, and TGA. Shown are target profiles of APP combination examples based on CLZ, RIS, HAL, CAR, QUE, OLA, and ARI displayed in a cobweb design. For further explanations, see legend to Figures 4, 5.

Figure 7. Data from a case report of CAR add-on to CLZ treatment. Shown is a brief schizophrenia treatment history of a female and a male patient prior to APP add-on with CAR to ongoing CLZ treatment. The accompanying graphs illustrate PANSS scoring and BMI observations evolving over time following start of the CAR add-on intervention [data extracted from De Berardis et al. (16)].