Table 1.

Map design principles.

The following principles determined drug locations, colours, groupings, connections and additional mechanistic information for the simplified (Figure 1) and full (Figure 2) versions of the map. All symbols described in this table are illustrated in the figure legends. Drug locations and colours • Drugs were represented by coloured discs (akin to a ‘station’ of a subway map), with disc colour determined by the chemical structure. Five drugs no longer available in most or all markets were distinguished by their discs having a white centre and appear in italic script. • Position on the east–west axis was established by the year first brought to market. • Position on the north–south axis was determined by the affinity for the dopamine D2 receptor, inversely proportional to the inhibition constant (Ki) – that is, lower affinity at the top of the page. Ki values were sourced from human studies of D2 receptor affinity listed in the Psychoactive Drug Screening Project (PDSP) database or if not listed in PDSP from published literature. Drug groupings: zones and interconnections between drugs • Drugs were grouped into zones corresponding to (1) first-generation (conventional), (2) second-generation (atypical) and (3) third-generation (dopamine D2 partial agonist) agents. • Solid coloured lines were employed to indicate commonly used groupings irrespective of their basis.  ◦ For first-generation agents (zone 1), this was based on long-established structure-based categories, for example, phenothiazines (subdivided into aliphatic phenothiazines (maroon) connected by dashed lines to the related piperidine (pink) and piperidine (purple) phenothiazine types), butyrophenones (light green), thioxanthenes (red), benzamides (silver) and diphenylbutylpiperidines (brown).  ◦ Clozapine and most drugs brought to market after 1985 are commonly grouped together in a ‘second-generation’ or an ‘atypical’ (zone 2) category and were connected by pale blue solid lines. As classification by structure is possible (but rarely used), we denoted second-generation drugs as benzisoxazoles/benzisothiazoles (green), benzamides (silver) and phenylindoles (dark blue), while some second-generation drugs and the first-generation drug loxapine can be described as having a tricyclic structure (black). Here, drugs sharing similar chemical structures were connected to each other with the weaker dashed lines.  ◦ Dopamine D2 partial agonist drugs, ‘third-generation’ drugs, were depicted in orange (also representing the rarely used structural description of phenylpiperazines/quinolinones) and form the map’s zone 3.  ◦ Pimavanserin, a serotonin-receptor modulator which does not belong to any of the three drugs groups described, was placed in an inset box at the top of the map due to negligible affinity for the dopamine D2 receptor. • Pairs of closely related drugs differing only by stereoisomer content or by one being an active metabolite of another were connected by double lines to emphasize their close connections. Additional mechanistic information • D2 partial agonists (aripiprazole and related ‘third-generation’ drugs) were marked with a star symbol on the station disc to emphasize the difference in their mechanism from D2 antagonist first-generation and second-generation drugs (both figures). • Symbols adjacent to each drug name provide additional information on drug mechanisms (Figure 2 only, with exception of cariprazine’s D3 affinity as a partial agonist being illustrated on both figures by an inverted triangle). • For six further receptors of interest (5HT2A, 5HT2C, H1, alpha 2 and M1/M4 cholinoceptors), additional symbols adjacent to the drug name were added (Figure 2 only). The final median Ki value from PDSP was represented by a solid triangle; large, medium or small size depending on affinity (strong: 0–19.99 nM, medium: 20–99.9 nM and weak: 100–999.9 nM). Where the Ki was ⩾1000 nM, a small circle containing an oblique line similar to a ‘zero’ was used. • Where no human data were available in PDSP but animal data were listed, hollow triangles of comparable size to those described above or for Ki ⩾ 1000 nM a small circle containing a vertical line were used to represent affinities. • Inverse agonist properties were denoted by a rectangle.