Advances in psychiatric treatment (2012), vol. 18, 337–350 doi: 10.1192/apt.bp.111.008920

Meet the relatives: a reintroduction article to the clinical pharmacology of ‘typical’ antipsychotics (Part 2)† David Cunningham Owens

Flupentixol (flupenthixol) (Table 1) David Cunningham Owens is Summary Professor of Clinical Psychiatry at This second of two articles on the ‘typical’ Flupentixol is the thioxanthene analogue of the University of Edinburgh and an (‘first-generation’) antip­ sychotics covers non- fluphena­zine and, although mainly used in the honorary consultant psychiatrist at the Royal Edinburgh Hospital. He phenothiazines: thio­xan­thenes (flupentixol and UK in its decanoate formulation as a depot, is trained originally in general medicine zuclo­penthixol), butyrophenones/diphenyl­ ­butyl­ also available (as dihydrochloride) in tablet form, and neurology before turning to piperidines (including one-time world market- a presentation traditionally popular with general psychiatry, where his interests leader haloperidol, and pimozide) and sulpiride, practitioners. have revolved around the biological for many years the only substituted benzamide Flupentixol (along with fluphenazine) is among basis and treatment of psychotic disorders, especially schizophrenia. available in the UK. Several tolerability issues the most potent of all antipsychotics. This, ascribed specifically or more frequently to older He is a member of the teaching combined with a relatively benign general adverse faculty of the British Association antipsychotics are also discussed. effect profile, makes it one of those antipsychotics for Psychopharmacology and of the Declaration of interest most likely to be subject to unnecessary dose UK drug regulatory authority, the Commission on Human Medicines. None. escalations. Minimum effective dose and true Professor Owens is one of the equivalence are therefore hard to assess. Usually few remaining clinical academics assumed to be around 50 times more potent than in the UK to partake in routine general adult psychiatric practice. This is the second of two articles reviewing the chlorpromazine (Atkins 1997; Gardner 2010), in Correspondence Professor antipsychotic drugs often referred to as ‘first- reality the figure may be closer to 100 times (Wyatt David Cunningham Owens, Royal generation’, ‘conventional’ or ‘typical’ – in reality, 1976). Certainly, even taking a conservative view Edinburgh Hospital, Kennedy Tower, compounds marketed before 1993. The first article of its relative antipsychotic potency, the British Morningside Terrace, Edinburgh considered phenothiazines (Owens 2012, this issue). EH10 5HF, UK. Email: david.owens@ National Formulary (BNF) recommendations of ed.ac.uk Here, I review the thioxanthenes, butyrophenones up to 18 mg/day for oral use still seem excessive (plus the closely related diphenylbutylpiperidines) (British Medical Association 2012). Its half-life † and substituted benzamides currently available (~19–39 h) makes it comfortably suitable for once- See pp. 323–336 and 351–352, this issue in the UK in oral formulations. As maximising daily dosing (Jorgensen 1980). prescribing choices depends on an individualised a. The cis /trans system by which In addition to powerful D2 actions, flupentixol ‘risk–benefit appraisal’, the article also considers these isomers were originally known has anti-serotonergic (5-HT2) and anti-adrenergic (Johnstone 1978) is ineffective for safety and tolerability issues more prevalent (predominantly a1) actions, but its activity at describing side-chain attachments or reported more frequently with the older cholinergic sites is too little to be clinically with more than two substituents on compounds. relevant (Fig. 1). It can therefore be associated a double bond. For complex organic compounds such as antipsychotics, with hypotension on first oral exposure and with the Z (zusammen, Ger: ‘together’: = T hioxanthenes extrapyramidal side-effects, though with gradual cis) /E (entgegen, Ger: ‘opposite’: = Thioxanthenes were synthesised in Denmark introduction and doses kept low, it is generally well trans) nomenclature was adopted. in 1958 and represent only a slight structural tolerated.b b. The BNF is confused on dosing and indications for oral flupentixol, which modification to the phenothiazine molecule. Flupentixol has the greatest D1 antagonist is listed under both antipsychotics However, the substitution of carbon for nitrogen activity of all the older antipsychotics. The signifi­ and antidepressants. In the latter at position 10 means that these molecules exhibit cance of this is unclear for, clinically, it does not case, a dosage of <3 mg/day is stereoisomerism – i.e. R substitutions can attach stand out as correspondingly different – apart recommended,­ but the indications 2 are ‘depressive illness; psychoses’, in mirror-image ways. The pharmacological from in one possible regard. Flupentixol has long without explanation of whether consequence is substantial, in that only one isomer been associated in low dose with antidepressant ‘psychoses’ here means ‘affective a psychoses’ or ‘psychoses in general’. (the cis or Z ) is an effective D2 dopamine receptor and anti-anxiety actions (Reiter 1969; Hall 1973; antagonist. Although widely used internationally, Predescu 1973; Frolund 1974; Gruber 1991). Most As reference to the antipsychotics section listing for the drug indicates, the first thioxanthene, chlorprothixene, was not reports are anecdotal (e.g. Trueman 1974; Becker the BNF would consider 3 mg/day marketed in the UK. 2002) or find easy explanation in different dose very low for schizophrenia.

337 Owens

regimes between flupentixol and comparator g g in

m drugs (Wistedt 1983), but a clinically impressive

m

antidepressant action has been demonstrated in good trials. In a two-arm non-placebo- controlled study, Young et al (1976) found that in mild to moderate depression, flupentixol had g every 5–7 days m antidepressant efficacy comparable to that of amitriptyline, with greater anti-anxiety effects. g m

In terms of quality of life, Hertling et al (2003) b dosing

a

g twice daily for 5–7 days found that people with schizophrenia treated g daily for 5–7 days, then increments g daily for 5–7 days, then increments m

g at similar intervals m m

with flupentixol felt subjectively more relaxed m

g probably excessive. Aim for 60–80 g atg intervals similar g daily probably excessive). Evaluate after m

m

and better able to deal with stress than those on m

of 1–3 For psychosis For Initial: 3 of recommendations Therapeutic: unknown (BNF 18 stability on 6–9 depression For Suggested Initial: 10 Then, increase by 10–12 (with chronic dosing, once-daily administration should be possible in most instances) of max recommendation Therapeutic: BNF 150 first instance and assess daily Initial: 1 0.5 Therapeutic: BNF recommendations: max 3 risperidone. We have seen similar claims for many early anti­psychotics, especially when the search for marketable indications was active (Owens 2012, this issue). However, a reputation for beneficial mood actions must surely have stuck to flupentixol longest and most consistently – perhaps sufficiently s

on so to accept the claim as valid. This is the only Very high potency Few general side-effects: easy for doses to be escalated beyond EPS threshold Likelihood of adverse symptom persistence for prolonged periods (long potency)half-life/high No clearly established dose regime for psychosis C Very sparse database to support action antipsychotic with oral formulation very data Dose-response weak older antipsychotic with UK approval for use in h depression. In line with recent trends, such affective benefits have been attributed to serotonergic actions (Becker 2002), but autoreceptor effects

– presynaptic D1 antagonism diminishing tonic inhibition of the transmitter synthetic enzyme lear antidepressant antidepressant lear C actions, at least in mild to moderate disorder Long-established use, especially in primary care High margin of safety Data (which are scant) dosing once-daily suggest appropriate: half-life ~35 Pros High margin of safety Refined isomer(more action) focused sedative Mildly Half-life (~20 hours) suggests single dosing possible with repeat administration tyrosine hydroxylase (or 3-monooxygenase) –

a highlighting as they do a prominent action of Z, P

C flupentixol, would seem worthy of consideration. mg mg

1.5–2 However, the notion that flupentixol’s clinical

favour a (clinical) (clinical) Refined:16 low-dosage equivalence assumptions Suggested 100

potency drug, pharmacology might allow it to be considered a As an ultra-high (racemate: 32.5)(racemate: interpretation of interpretation of equivalence to ‘partial atypical’ antipsychotic (Rachid 2004) is to turn the taxonomical embarrassment of ‘atypicality’ (Owens 2008) seriously surreal. ­ pyramidal Very high Moderate tra Zuclopenthixol (zuclopentixol) (Table 1) x E Clopentixol, the thioxanthene analogue of perphenazine, was introduced in the early 1960s, Low Low with the literature repeating an established General ability to non-target actions

i pattern – therapeutic benefit in chronic schizo­ L phrenia unresponsive to other medications (Ban inical pharmacologyinical

l 1963; Wolpert 1967). As with flupentixol, it was C re Narrow Narrow

B originally presented as a racemic mix which,

­ like flupentixol, has a striking impact on its ­ ics) ) adth 2

hot pharmacology (Johnstone 1978). The pure trans ceptor binding (D e Potency Very high R

of anti all (E ) isomer, with minimal dopamine antagonistic (one of the psyc most potent Intermediate activity, has little antipsychotic action, although it is highly sedative. Mixed racemates (e.g. ­ pentixol) clopentixol tablets, which have a trans :cis ratio of 2:1) share this sedative property, whereas purer (flupenthixol) Drug Zuclopenthixol Zuclopenthixol (zuclo -phenothiazine older antipsychotics for oral use: thioxanthenes antipsychoticsuse: oral -phenothiazine for older cis isomers (e.g. Clopixol® depot, with a trans :cis on

N ratio of 1:49) do so to a lesser degree (Nolen 1983). Furthermore, while the pure cis isomer was found to have the same antipsychotic effect, on Thioxanthenes Flupentixol Group table 1

BNF, BritishBNF, National Formulary; CPZ, chlorpromazine; EPS, extrapyramidala. Suggested side-effects. values are based on minimum effective doses in the literature and on the author’sb. Despite experience. established efficacy of flupentixol for mild to moderate depression, antipsychotics carry an inherent risk of EPS (especiallya tardive dyskinesia) not in general shared by antidepressants.mg/mg basis it was approximately twice as active

338 Advances in psychiatric treatment (2012), vol. 18, 337–350 doi: 10.1192/apt.bp.111.008920 Meet the relatives: Part 2

as the trans (Gravem 1978). The purified cis isomer D (subsequently renamed the Z isomer, incorporated 1 D in the marketed name, zuclopenthixol) was 2 5-HT introduced to the UK in the late 1970s and is now 2 a the only form available. 1 Although refining the product increased potency ACh H and reduced the adverse effect profile, it did not 1 abolish tolerability problems. Zuclopenthixol, Chlorprothixene Flupentixol Zuclopenthixol perhaps because of its mild antihistaminic action, remains a more sedative preparation fig 1 Receptor binding profiles of some thioxanthene antipsychotics by percentage of total than flupentixol (even comparing depot formats) binding contributed to by each transmitter type (after Hyttel 1985). and, with little antimuscarinic activity, is prone to promote extrapyramidal side-effects (EPS) Paul Janssen’s interest in the effects of physical above a certain threshold, though these may be properties on complex organic molecules. By less persistent during acute treatment than those subjecting pethidine (meperidine) to heat, he associated with haloperidol (Heikkila 1992). created nor- (or desmethyl-) pethidine, which Unfortunately, that threshold is hard to when itself heated, transformed more or less to determine as, once again, the dose-finding literature haloperidol. By 1988, the 30th anniversary of for oral formulations is poor, a particular problem this elegant finding, haloperidol was the world when constituent components have changed. Older market-leader antipsychotic in sales terms. What publications suggest chlorpromazine:clopentixol was not clear was how much its widespread use in equivalence at between 4:1 and 5:1 (Wyatt 1976; US emergency rooms contributed to stellar sales, Rey 1989), though a more recent perception is of although by the late 1980s the shift in American greater relative potency (~10:1; Gardner 2010). psychiatry towards high-potency antipsychotics Some early trials utilised restraint in dosage (e.g. – and its detrimental consequences in terms of Wolpert 1967: 50 mg/day), but most studies on increased liability to extrapyramidal side-effects which equivalence tables are based used much – had already been highlighted (Baldessarini higher doses (e.g. Serafetinides 1972: average 1984). The prominence haloperidol still holds in 227 mg/day). The problem of older studies using US practice can be seen in more recent consensus racemic mixes in which sedative properties may equivalence recommendations (Kane 2003), which have contributed to the therapeutic ‘package’ is are based on this, and not chlorpromazine, as the insurmountable, and zuclopenthixol equivalence standard.c There is, of course, no reason why c. Cementing the US trend away at, say, 8:1 (Gardner 2010) is largely guesswork. haloperidol should not be considered the standard from chlorpromazine as reference antipsychotic, Gardner et al Certainly, the drug is best considered as of antipsychotic for reference purposes – provided (2010) also chose as the standard intermediate potency (doses in tens of milligrams one can be confident that this is a drug that haloperidol for parenterals – and per day; see Owens 2012, this issue), with efficacy clinicians have traditionally used thoughtfully, olanzapine for orals. likely at the lower end of BNF recommendations with restraint. The evidence does not support such (i.e. ≤ 80 mg/day) and possibly as low as 60 mg an assumption (Owens 2008). (Gardner 2010). The BNF also places a single- dose restriction (40 mg) on zuclopenthixol (British Haloperidol (Table 2) Medical Association 2012). Although somewhat Haloperidol was traditionally referred to as a more active at noradrenergic sites than flupentixol, ‘selective’ dopamine antagonist (Hyttel 1985) clinical experience would not suggest particular and, although there is some truth to this, others blood pressure concerns to justify such caution, can lay better claim to the title (see below). It especially with repeat dosing. is, however, active across the dopamine receptor Unlike injectable formulations, oral zuclo­ family, and at D2 subtypes in particular produces penthixol has never enjoyed prescribing among the greatest affinities of any antipsychotic. prominence with psychiatrists in the UK, for It has modest 5-HT2A actions and slightly greater reasons that are not clear. Nonetheless, with a affinity for a1 receptors (Fig. 2). As a result, it mildly sedative profile and wide dose range, tablet can be associated with hypotension, though this formats have probably been underutilised in is usually mild, restricted to postural effects and specialist practice. rapidly habituates. For this reason haloperidol, along with other butyrophenones, has long been B utyrophenones (phenylbutylpiperidines) seen as suitable for parenteral administration, Haloperidol, the foundation butyrophenone, though the intravenous route should always be was discovered through the pharmacologist used with care and appropriate monitoring.

Advances in psychiatric treatment (2012), vol. 18, 337–350 doi: 10.1192/apt.bp.111.008920 339 Owens g m

g) m

b g/day) as g every 7–10 m

m

g at night g at similar intervals m m

dosing g 3 times a day or 0.5 a m g daily for 7 days

g/day m

g if possible (when con- g: if no/partial response after m

m

m

g/day in first instance m mg/day)

twice a day + 1 Aim to assess efficacy in doses ≤5 Initial: 0.5 Assess over 5–7 days, then incre- ments of 0.5–1 up to 5 Therapeutic: consider BNF recom- mendations (up to 30 very high 5–10 4–6 weeks, can be increased (up to 15 concomitant prescribe Always anticholinergics Watch for acute dystonias and akathisia, especially adolescents in Suggested Then, increase by 2 Initial: 2 days Therapeutic: keep daily doses ≤6–8 comitant anticholinergics may not be necessary) BNF max recommendation (20 should be viewed as high (unless as part of a planned ‘intermittent strategy) exposure’ - ­ s on ology suggests (strong Perceived as an easy drug to use, obscuring the reality Very high potency/affinity Very high (? unique) liability to promote EPS Likelihood of adverse symptom persistence for prolonged periods (months) perception Professional of dosage substantially higher than pharma c tendency overuse) to C Ion channel activity may increase risks: implicated in sudden death at high dose specifi monitoring ECG recommendedcally High EPS liability with symptom durability (months) h)

Long-established use Long-established Very high margin of safety Relatively low liability to general adverse effects, making parenteral use feasible (with caution): thus, invaluable in prevention/management psychiatric of emergencies Pros antipsychotics (50+antipsychotics Been shown in controlled randomised trials to be suitable for intermittent dosing ? Particular advantage with adherence poor

a Z, P C mg mg 1–1.5

(clinical) (clinical) Suggested 100 1 (possibly 1.5) Longest half-life of old equivalence to ­ pyramidal (possibly Very high Very high tra the greatest liability of all x antipsychotics) E Low possible Low (but General ion channel ability to non-target actions antagonism) i L - inical pharmacologyinical l C Very tive’) re selec narrow (‘highly Narrow B ­ ics) ­ ) adth 2 hot ceptor binding (D e all anti Potency R Very high Very high highest of (among the psyc Haloperidol Drug Pimozide ­ ­ ­­ butyl ­ butyl ype iperidine iperidine p Phenyl T Diphenyl p -phenothiazine older antipsychotics for oral use: butyrophenones antipsychoticsuse: oral -phenothiazine for older on N Butyrophenones Group table 2 BNF, BritishBNF, National Formulary; CPZ, chlorpromazine; ECG, electrocardiogram;a. Suggested EPS, extrapyramidal values are based on minimum side-effects. effective doses in the literature and on the author’sb. Haloperidol experience. has a long half-life and is easily suited to once-daily dosing. Spreading doses during acute treatment may help control non-specific symptoms.

340 Advances in psychiatric treatment (2012), vol. 18, 337–350 doi: 10.1192/apt.bp.111.008920 Meet the relatives: Part 2

The drug has no significant antihistaminic or D antimuscarinic actions (Chew 2008). This lack 1 D of inherent anticholinergic activity could, in 2 5-HT such a potent dopamine antagonist, account for 2 a1 a high liability to EPS and an accordingly poorer ACh performance compared with other antipsychotics H with broader binding profiles (Rosenheck 2005). 1 Haloperidol is, however, also among the most Haloperidol Droperidol active compounds at sigma-1 (s1) receptors fig 2 Receptor binding profiles of two butyrophenone antipsychotics by percentage of total (Largent 1987; Cobos 2008) and, although the binding contributed to by each transmitter type (after Hyttel 1985). clinical significance of this remains unclear, it has been suggested that these receptors play a role in can be attained with doses lower than 5 mg/ control of voluntary movement, especially through day (Rosebush 1999; Oosthuizen 2001) and that modulation of muscle tone. such regimes are confirmed by functional brain

Haloperidol is the high-potency antipsychotic imagining to achieve the desired D2 occupancy of par excellence, with all the advantages and dis­ < 80% %, thereby avoiding EPS (Kapur 1997). A advantages that come with that sobriquet. The relative potency of 50:1 can be inferred from Davis advantages lie with a therapeutic index that is highly & Chen (2004), but even these authors acknowledge favourable – the drug retains a remarkable margin that 3.3–4 mg/day was the near-maximal effective of safety over a seemingly limitless dose range. At dose range. Thus, it may be more appropriate the 30th anniversary meeting held in Antwerp to consider chlorpromazine:haloperidol relative in 1988, the pioneering psychopharmacologist potency as closer to 100:1, acceptance of which Dr Frank Ayd caught his audience’s attention by would demand a considerable shift in clinical describing a patient who received over 700 mg practice. in 24 h! In translating a therapeutic index to Acute (single) dosing studies suggest that practice, however, excellent safety becomes all too haloperidol has a half-life between 14 and 36 h often confused with excellent tolerability – and (Kudo 1999), making it comfortably suitable therein lies the core of the disadvantages. Because for once-daily dosing. However, as with other of its limited receptor binding profile, haloperidol antipsychotics, split dosing may be better for may be safe, but because of its exceptional anti­ managing non-specific symptoms. With repeat dopaminergic potency (and possibly actions at dosing, however, the half-life of haloperidol can be other sites), its EPS tolerability is very poor – extended considerably – in almost half of patients, perhaps uniquely so (Owens 1999) – making this, to longer than 3 days (de Leon 2004). Cumulation in my experience, a ‘difficult’ drug for doctors to may be another reason for the drug’s peculiar prescribe. proneness to EPS. Like many, I previously advised This aspect of ‘difficulty of use’ can be related to that anticholinergics should be prescribed only if evidence suggesting that, for maximal subjective and when EPS emerged (Owens 1999), but I would experience, a very low dose in the range of 2.5 mg now recommend, along with others (Rosenheck haloperidol achieves the ideal D2 occupancy (de 2005), that with high-potency, selective drugs Haan 2003). These data support the view that such as haloperidol, anticholinergics should be subjective effects of antipsychotics are indeed automatically co-prescribed (Owens 2010). extrapyramidally mediated and hence may reflect Butyrophenones are pharmacologically ‘much the inherent action of all compounds in the class of a muchness’. Droperidol, with similar nor­ (see Owens 2012, this issue). adrenergic and somewhat greater 5-HT activity Because haloperidol has traditionally been compared with haloperidol, was for many years used in unnecessarily – sometimes cavalierly a mainstay of emergency treatment in the UK. It – high doses, standardising dose equivalences fell for ‘commercial reasons’, but essentially on is difficult. Older American recommendations, the back of the same QTc concerns that killed based on studies at a time when restraint was more thioridazine (Reilly 2000, 2002). The extent evident, suggested a chlorpromazine:haloperidol to which this reflected the drug per se or the equivalence of about 40:1 (Wyatt 1976). With emergency (and often restraint) circumstances in the gradual increase in high-potency drug use, which it was used remains unclear (see below). equivalence favoured a 20:1 ratio. This tended to Benperidol, the only other butyrophenone avail­ be the benchmark adopted in most comparator able in the UK, has a similar profile to others of studies for new antipsychotics. However, we the group, although its antihistaminic and anti- know that therapeutic efficacy without EPS adrenergic actions are evident only at high dose

Advances in psychiatric treatment (2012), vol. 18, 337–350 doi: 10.1192/apt.bp.111.008920 341 Owens

(Schwarz 2005). Popular in some continental Its blockade of transporter proteins (especially the countries, especially Germany, it never found serotonin and dopamine transporters), although favour as an antipsychotic in the UK and is some­ less than that of antidepressants, might have what misclassified in the BNF. Here, its use has accounted for an ‘alerting’ action, but yet again largely been restricted to controlling excessive such action did not withstand closer scrutiny (Sims or deviant sexual behaviour (as a so-called anti­ 1975; Wilson 1982). The proposal that pimozide libidinal) (British Medical Association 2012). could also be an effective treatment for tardive It seems unlikely that its actions in this regard, dyskinesia likewise fell, any benefits probably poorly established anyway, are unique, while arising simply from suppression with the use of its cost (some 50 times that of the very similar relatively large doses (Owens 1999) or masking by haloperidol) is exorbitant for a drug on the market Parkinsonism (Claveria 1975). for over 40 years. Its persistence is probably an Even in the more restrained prescribing historical anomaly and its cost-effectiveness hard atmosphere of the 1970s, pimozide was considered to envisage. to have a chlorpromazine-equivalent potency of approximately 80:1 (Wyatt 1976), an assessment Diphenylbutylpiperidines that has held (Gardner 2010), though this is not a Only a relatively minor modification of the butyro­ drug licensed or much used as an antipsychotic in phenone (or phenylbutylpiperidine) molecule the USA. A more conservative assessment might produces the diphenylbutylpiperidines. These rate its potency as high as 100:1 to 150:1. This, are therefore hardly a separate chemical group, combined with a long half-life (~50 h, sometimes although they are characterised by the longest greatly extended to 150 h) is relevant to the half-lives of any of the older antipsychotics. fact that pimozide is the only orally formulated antipsychotic whose value has been demonstrated Pimozide (Table 2) convincingly with other than daily use. Given Pimozide can lay better claim to being a on 4 days a week, McCreadie et al (1980) found that it was as effective in maintenance as depot ‘selective’ D2 antagonist than haloperidol (Fig. 3). It is probably the most potent of the currently fluphenazine. In an intriguing study, it was then available antipsychotics, with powerful affinity given once weekly to a group of in-patients using the same comparator (McCreadie 1982). On the for D2 receptors, in contrast to negligible D1 and muscarinic cholinergic actions. It does interact basis of prior treatment regimes, doses ranged from 10 to 60 mg pimozide once weekly. Over a weakly at 5-HT2 and to a lesser extent a1 sites, 9-month period, there was no difference in relapse though its affinity for histamine 1H receptors is minimal (Sekine 1999). Furthermore, pimozide rates between the groups. Blood monitoring has significant calcium channel antagonist showed a peak at 8 h, with return to more or less properties (Galizzi 1986), implicated in both pre-administration levels after 4 days. favourable (mood elevating) and unfavourable The study’s authors suggested that weekly treat­ (cardiac) actions. It is also one of only a handful ment is genuinely ‘intermittent’ treatment. ‘Drug of antipsychotics to inhibit biogenic amine holidays’ (when treatment is temporarily suspend­ transporters to a potentially clinically significant ed) were once popular for minimising exposure degree (Tatsumi 1999). and reducing the risk of tardive dyskinesia Pimozide was one of a small number of drugs but fell into disrepute when the opposite was originally thought to be ‘novel’ (Owens 2008) demonstrated – namely, an increased risk of this and its use was initially targeted on ‘activating’ side-effect (Jeste 1979). McCreadie and colleagues withdrawn individuals with chronic schizophrenia. did record increased tardive dyskinesia ratings in their pimozide group, although this may have represented ‘withdrawal-emergent’ rather than the prognostically more sinister ‘treatment- D 1 emergent’ disorder. Two important findings were D 2 that elevations in prolactin were maintained only 5-HT 2 within a 48 h window post-administration, possibly a 1 suggesting lower hyperprolactin-related side- ACh effects, and that substantial weight loss (on average H 1 12 lb or 5.4 kg) occurred in the pimozide group. Pimozide Penfluridol Fluspiriline Penfluridol and fluspirilene This work highlights a fig 3 Receptor binding profiles of some diphenylbutylpiperidine antipsychotics by percentage long-held dream – an oral antipsychotic suitable of total binding contributed to by each transmitter type (after Hyttel 1985). for once-weekly maintenance. Penfluridol (Fig. 3)

342 Advances in psychiatric treatment (2012), vol. 18, 337–350 doi: 10.1192/apt.bp.111.008920 Meet the relatives: Part 2

once encapsulated this but was withdrawn from perverse that it should be proposed by some as most markets on safety concerns. As the above being ‘atypical’ (Naber 2009). suggests, the value of such strategies might Elegant theories (e.g. limbic selectivity of action) extend beyond patient preference to encompass have been constructed to explain this paradox, real medical advantages. Pimozide was, however, though an alternative pharmacokinetic explanation one of the first antipsychotics to become ensnared must not be discarded merely because it is simpler. in the ‘sudden death’ issue (Committee on Safety In vitro D2 binding suggests that sulpiride should be of Medicines 1990), with subsequent upper limits considered of intermediate potency, yet clinically on daily dose (20 mg) recommended in the BNF. It it must be used in high – for an antipsychotic, is doubtful whether the doses in the above study sometimes ultra-high – doses to achieve efficacy. (mean single weekly dose of 40 mg) would be Benzamide is a poorly soluble substance and, unlike acceptable now, at least without monitoring. The most antipsychotics, sulpiride is predominantly same principle may, however, be worth exploring water, not lipid, soluble. As a result, its low bio­ with newer drugs with very long half-lives (e.g. availability (~30%) reflects poor absorption not, aripiprazole). as with most antipsychotics, heavy presystemic A further unrealised dream is that of a specific metabolism and/or wide distribution (Wiesel 1980; antipsychotic for a specific mental state disorder, Owens 1998). Such absorption as does occur seems though pimozide still clings to its reputation of to take place via the clumsy mechanism of two possessing particular efficacy in monosymptomatic sequential zero-order (i.e. saturable) processes hypochondriacal psychosis and related disorders (Bressolle 1992). That which is absorbed faces (see the BNF). This view sprang largely from the the further challenge of crossing the blood–brain work of a single Canadian group (Riding 1975a,b) barrier. It is to overcome these disadvantageous and related to small numbers of patients. It lacks kinetic properties that high doses are required. clinical credibility and, if one classifies disorders of This is a difficult drug to use in ‘dose equivalence’, this type as ‘delusional disorder’ variants, does not as switches are likely to represent overall dose stand literature review either (Manschreck 2006). reductions from previous regimes, a point illustrated Fluspirilene (Fig. 3) was withdrawn in the UK by the very low doses (~300–600 mg/day) now seen a number of years ago but is of interest as being by specialists as appropriate (Gardner 2010). This technically the first ‘long-acting injectable’ (LAI) is likely to be a significant reason for sulpiride still (for the distinction between ‘LAIs’ and ‘depots’, see being considered ‘atypical’ – as it was 40 years ago Owens 2010). It is a very poorly investigated com­ (Owens 2008).d d. Such an explanation is even more pound, but at approximately 3 weeks, its half-life Sulpiride’s unusual and poorly acknowledged worthy in regard to amisulpride, whose D2 (and D3) binding would appears to be the longest of any antipsychotic. It kinetics is one factor underlying a lack of consensus suggest very high potency, is water-insoluble and requires parenteral admin­ on equivalent dosing. Chlorpromazine:sulpiride something not borne out by clinical istration, but given weekly as an aqueous particle equivalence is usually taken as being in the range experience. suspension is as effective as depots (Abhijnhan of 1:2 to 1:3 (Rey 1989; Atkins 1997), which would 2007). Its half-life suggests that an even longer make an upper recommended dose of around 800– interval between injections may be possible. 1200 mg/day (maximum ~1500 mg). However , this remains a drug about which clinicians show Substituted benzamides confusion. While estimating sulpiride to be only Manipulations of the benzene ring have proved 75% as potent as chlorpromazine, experts then productive routes to drug development in many suggested an identical target dose range (300– branches of medicine. Sulpiride, the most durable 600 mg/day) for the two (Gardner 2010). The very antipsychotic of the group, is a modification of the anti-emetic metoclopramide, itself a modification D of procainamide. 1 D2 5-HT Sulpiride (Table 3) 2 a Sulpiride is the embodiment of the highly selective 1 ACh D2 antagonist approach to ‘anti-psychosis’ (Fig. 4). H1 With no appreciable actions at D1 or D4 sites, limited actions at D3 (Strange 2001) and only the Sulpiride weakest at 5-HT and a receptors (not clinically 2A 1 fig 4 Receptor binding profile of the substituted benzamide significant), it is the validation in practice of antipsychotic sulpiride, by percentage of total binding the ‘classical’ dopamine antagonist hypothesis contributed to by each transmitter type (after Hyttel of antipsychotic action. It may therefore seem 1985).

Advances in psychiatric treatment (2012), vol. 18, 337–350 doi: 10.1192/apt.bp.111.008920 343 Owens

high upper dose recommended by the BNF (2.4 g/ day; British Medical Association 2012) is likely

g/day (if (if g/day to reflect a left-over from early studies, some of m

which utilised up to 3.2 g per day. The value of ‘mega-doses’ has not been demonstrated and must at similar b

g be suspect, especially in view of the saturable m absorption mechanism. Although calculated values are discrepant, twice a day for 5–7 days b

dosing sulpiride is a drug of relatively short half-life g/day: max ~1200–1400 max g/day: a mg

m for an antipsychotic (~6–8 h) (Jorgensen 1986) , consider adverse pharmacokinetic g and ideally should be given a minimum of three times daily. Despite this, twice-daily regimes have Suggested necessary to go to the BNF recommended limit of 2.4 intervals recommendations BNF Therapeutic: Consider as high 600–1000 factors acting against maximising therapy) Poor response: consider splitting dose further (3 times a day) Watch for signs of hyperprolactinaemia Initial: 200 Then increments of 200 become the norm but on the basis of convenience/ adherence rather than kinetics. Sulpiride can be sedative in some patients, an effects effects 2 action that does not find ready explanation in its known pharmacology nor, as it is largely excreted unchanged, in its metabolism. Moving beyond

s common receptor types, however, substituted on Short half-life and poor kinetics: split dosing necessary which, strictly, should be 3 times a day Particular? liability to promote hyperprolactinaemia regimes, high-dose Despite which imply low potency, persistence of D C (affinity in reality high) benzamides interact with the g-hydroxybutyrate (GHB) receptor (Ratomponirina 1998), which may have a bearing on sedative actions. Sulpiride also produces higher prolactin levels than other, broader- spectrum antipsychotics (Mannisto 1978; Harnryd 1984), something clinicians have long been aware of in increased rates of galactorrhoea. Extrapyramidal side-effects may not be the only non-target actions Excellent general and EPS tolerability Low doses may have presynaptic preferential (autoreceptor) actions, promoting better engagement Pros open to amelioration by broad receptor interactions,

a

g only). and brisk prolactin response may be the price that Z, m

P

C comes with high D2 selectivity. In this regard, the mg 210 mg highest prevalence rates for hyperprolactinaemia may be in view of (clinical) (clinical) approximate approximate Suggested 100 unpredictable be considered have been reported with amisulpride (Bushe 2008), as high as 250) (estimates must as low as 130 or equivalence to unfavourable and pharmacokinetics: its close relative with even greater D2 affinity and dopaminergic selectivity.

Prescribing older antipsychotics: safety Low ­ pyramidal

tra and tolerability x E Antipsychotic prescribing, like all prescribing, involves an appraisal of risk run against benefit accrued (Owens 2008). At a population level, justi­ Very low General

ability to non-target actions fica­tion for antipsychotic use is easy. Untreated i L patients with schizophrenia have a reduced life 2 expectancy compared with treated patients inical pharmacologyinical l (Tiihonen 2009). Seen through this lens, ‘benefit’ C Most Most re B

antagonist is so massive as to easily outweigh not only selective D selective Very narrow ) adth 2 tolerability but even safety issues for the class as a whole. Clinicians, however, must practise through a ceptor binding e High R

by very more sensitive lens – that focused on the individual modified modified (but effect properties) poor kinetic

Potency (D suffering an illness defined by its own individual characteristics. With the evidence now pointing to the irrefutable fact that antipsychotics do not differ -phenothiazine older antipsychotics for oral use: substituted antipsychoticsuse: oral -phenothiazine for older benzamides Sulpiride Drug meaningfully in either efficacy or effectiveness, on

N tolerability becomes key to ‘tailored’ prescribing. Some adverse (or ‘non-target’) effects have been mentioned, especially those relating predictably to Substituted Substituted benzamides Group table 3

CPZ, chlorpromazine; EPS, extrapyramidal side-effects. a. Suggested values are based on minimum effective doses in the literature and on the author’sb. Difficult experience. drug to ‘fine-tune’ maximally at the lower end of dose range in view of restricted tablet strengths (200 and 400 receptor actions, such as sedation and hypotension.

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Overall, however, the list of potential tolerability are administered, can itself be associated with QT issues is long (see Owens 2010) and only a few prolongation (Bar 2007). This is thought to result significant concerns of greater relevance to older from decreased parasympathetic modulation, drugs will be raised here. which in turn exposes the heart to unopposed sympathetic drive (‘sympathetic prolongation’). QTc and sudden death The loss of protective vagal modulation has been Twenty-five years ago the American Psychiatric correlated with the severity of positive psychotic Association set up a working party to look at sudden symptoms and duration of illness (Bar 2005). death syndrome (SDS) occurring in individuals The circumstances associated with administering taking psychotropic medications (Simpson 1987), antipsychotics may thus confound the relationship though with antipsychotics the concern was long- between them and sudden death, something more standing (Hollister 1965). Although inconclusive, likely to ensnare older drugs, which remain the their report was followed by an expanding favoured compounds for controlling disturbed literature suggesting an association. A mechanism behaviour. Enforced restraint and tranquillisation was subsequently outlined in prolongation of the should always be viewed as major undertakings QTc interval (the cardiac repolarisation phase with the potential for serious consequences. corrected for heart rate), the risk emanating An electrocardiogram (ECG) as part of routine from the multifocal tachyarrhythmia, torsade de medical assessment represents good psychiatric pointes. The pharmacological basis is believed to practice. However, if the focus is solely the QTc, be blockade of the rapid component of the delayed there is no evidence that routine ECGs are effective in detection/prediction and they are certainly rectifier potassium (IKr) channel. It is now clear that patients receiving anti­ not cost-effective. Of far greater importance is psychotics can develop prolonged QTc (Reilly a detailed history, including prescription of QT- 2000; Ray 2001) and that all compounds share prolonging drugs, and – crucially – family history this potential. Furthermore, epidemiological of sudden premature death, heart disease and studies support an increased risk of sudden death so on. in those taking antipsychotics (Reilly 2002; Ray 2009). However, these facts do not necessarily tell Cerebrovascular events in elderly people prescribers all they need to know. In 2004, regulators received data from randomised Although QT prolongation may be the best controlled trials assessing the value of risperidone predictor of serious dysrhythmias, it remains for the behavioural and psychological symptoms of a weak one. It is an even weaker predictor of dementia (BPSD) that suggested an unanticipated sudden death (Shah 2005; Sager 2008), leaving increase in cerebrovascular incidents. Concern the literature difficult to interpret. For example, extended to other new compounds, raising the in Reilly et al ’s (2002) sample, groups were not question as to whether this was an issue with matched for exposure to diuretics, a major confound ‘atypicals’ or, of greater concern, an antipsychotic as hypokalaemia is known to prolong QTc (Witchel class effect. 2003); and although Ray et al (2009) established Subsequent data have been contradictory and important dose–response relationships, the ranges detailed exposition is beyond the scope of the devised bear little relationship to mainstream present article. However, epidemiological findings prescribing – unless antipsychotics are being used do support an increased risk of cerebrovascular for non-specific purposes in patients vulnerable events, comparable with newer as with older drugs to QTc prolongation because of, for example, (Trifiro 2009) and perhaps greatest in the early ischaemic heart disease. weeks of exposure (Kleijer 2009). The increased Sudden death has been reported more often with risk appears to hold when the focus is narrowed older drugs, but one must again interpret this with to stroke, though some findings suggest that the caution as it largely reflects frequency of use rather ‘atypicals’ do present a slightly enhanced risk than inherent risk. So-called atypicals are also (Douglas 2008). However, Sacchetti and colleagues implicated (Ray 2009). There is a further factor found the risk to be greatest (some sixfold) with that can confound any apparent increased risk phenothiazines and general frailty as opposed attributed to drugs, perhaps sufficiently powerful to dementia (Sacchetti 2008). These findings are to explain the fact that with sophisticated analyses, worth noting as the study included data for stroke independent effects of antipsychotics on QTc estimates in the unexposed elderly population that can be hard to demonstrate (Ramos-Rios 2010). matched well with data from other international ‘Hyperarousal’, especially in situations where work, suggesting that the group captured a emergency tranquillisation or high-dose regimes comprehensive sample. If true, this view weakens

Advances in psychiatric treatment (2012), vol. 18, 337–350 doi: 10.1192/apt.bp.111.008920 345 Owens

the perception of the likes of promazine as ‘benign’ photoallergy, with action in the UVA range, so and of especial utility for elderly people. brightness more than heat is what matters. It results Careful consideration must be given to prescrib- from UV-induced dissociation of the chlorine ions ing antipsychotics for older people, especially the which stimulate damaging free radical actions frail, with decision pathways clearly recorded. (Moore 2002). Barrier creams should be routinely available to those taking chlorpromazine and Venous thromboembolism those on other phenothiazines who develop itching Venous thromboembolism in patients on anti­ or burning. psy­chotics seems a lesser risk than was at one Antipsychotics can also produce toxic time thought, though recent work supports the suppression of bone marrow elements and, rarely, view that low potency is a factor, especially in severe allergic failure. Compared with the detail the 3 months after initiation (Parker 2010). The with which clozapine’s effects on marrow have most likely explanation links thromboembolic been charted, we know remarkably little about events to weight gain, immobility, smoking and the long-term effects of older antipsychotics. other lifestyle issues, but it remains possible that However, even if routine monitoring reveals blood with phenothiazines (especially chlorpromazine), parameters within the normal or low-normal production of clot-promoting anticardiolipin range, it is prudent to assume that in chronically antibodies is relevant. treated patients, marrow is under stress with long- term antipsychotic exposure of any kind, a fact to Allergic and toxic reactions bear in mind if clozapine-treated patients subject Virtually all antipsychotics have been associated to polypharmacy suffer a fall in their neutrophil with isolated reports of allergic reactions, but count and slip into ‘amber’ alert, when reducing/ the greatest risk lies with phenothiazines and, stopping all additional medication should be the because of the ongoing frequency of its use, with priority. chlorpromazine. A typical hot, itching, erythematous skin rash Hyperprolactinaemia coming on 10–14 days after first exposure and Rises in serum prolactin have been attributed immediately on subsequent exposure affects to all older antipsychotics, while much has up to 10% of patients. Hepatic dysfunction may been made of the newer drugs, where it seems show simply as deranged liver function tests or, in ill-sustained or even absent. The likelihood about 1% of individuals, frank jaundice. Although of hyper­prolactinaemia cannot, however, be often described as allergically mediated, this used to categorise antipsychotics into ‘typical’ cholestatic jaundice also comprises an element of or ‘atypical’. Those newer drugs for which the toxicity (Owens 1998). It is usually asymptomatic, phenomenon seems limited or absent are mostly of although it may be associated with nausea, fatigue, low potency with rapid dissociation characteristics

itching, etc. and, very rarely, can progress to acute (from D2) – essentially, clozapine and possibly liver failure. A biliary cirrhosis, generally less quetiapine. Others are lower-potency compounds sinister than the idiopathic variety, can also be a with broad binding profiles used in (relatively) serious medical development. low dose (e.g. olanzapine). A similar pattern Between 60 and 70% of patients on long-term would probably be expected with older drugs chlorpromazine develop autoantibodies, especially used with equal prudence. The clinical relevance antinuclear antibodies, and polyclonal immuno­ of hyperprolactinaemia has been cogently argued globulin M (IgM) elevations are commonly seen (Dursun 2008) but remains unclear. with phenothiazines in general (Canoso 1990). The long-term significance of immunopathic Extrapyramidal side-effects changes is unclear and although chlorpromazine Extrapyramidal dysfunction slipped (or was has been implicated in drug-induced systemic pushed) down the list of perceived problems lupus erythematosus, this is very rare and usually associated with antipsychotic drug use but – of relatively benign. course – never went away. Some ‘acute-end’ EPS, Phenothiazines in high dose over long periods especially acute dystonias, have undoubtedly can precipitate deposition of a melanin-like decreased in prominence with use of newer substance in soft tissues, including the skin, eyes drugs. This is probably related to a mixture of and internal organs (oculocutaneous melanosis). pharmacological differences (e.g. lower potency/ Many antipsychotics can sensitise to sunlight, greater breadth of receptor interactions) and use but again the major ‘culprit’ is chlorpromazine. in lower dose schedules than were previously This side-effect is a mixture of phototoxicity and in vogue for the older drugs. Differences in

346 Advances in psychiatric treatment (2012), vol. 18, 337–350 doi: 10.1192/apt.bp.111.008920 Meet the relatives: Part 2

usage might also explain diminution in rates of Thus, the key to maximising tolerability and tardive motor disorders, though reductions here ensuring minimum exposure with antipsychotics remain to be established. However, the major lies in the first few days of treatment. conceptual and practical EPS issue for clinicians is One notion that has, for a second time, fallen into Parkinsonism, because its pervasiveness and wide disregard is the ‘neuroleptic threshold’. This was boundaries have never been clearly acknowledged based on the simple, intuitive idea that once a cer- and clinical means of delineating it from illness tain D2 occupancy is passed one has moved beyond and other similar phenomena are without proven the necessary therapeutic dose into the realms of validity. Nonetheless, the evidence we have is that side-effects and that this transition can be detected Parkinsonism is as prominent a risk as ever (Miller clinically by the presence of subtle extra­pyramidal 2008). The reader is referred to my previous article signs, the most widely discussed being changes in in Advances (Owens 2008) for why this remains of handwriting (Haase 1961). Once these, or any clini- the utmost importance and to specialist sources cal markers of extrapyramidal dysfunction, emerge for clinical accounts (e.g. Owens 1999). cautious reduction of dose should maximise the likelihood of benefit while minimising EPS risk. The ‘minimum effective dose’ Imaging work supports this principle (Farde While everyone agrees that treatment with 1992), and in the early 1990s these ideas were all antipsychotics should revolve around the revived only to sink again with the introduction ‘minimum effective dose’ (Tables 1–3), what of new agents, with their unjustifiable reputation that is and how to achieve it is usually unstated. for beneficence. The variability of handwriting With older antipsychotics, this is partly makes reliability an issue, but the principles of because we do not have the data necessary to not increas­ing to a new dose until the likelihood craft dosage ‘algorithms’ in the face of highly of EPS emerging can be assessed on the existing variable kinetic and response characteristics, dose, and not pushing doses beyond those that and partly because management policies act precipitate EPS, is a good framework for sound against ‘ideal’ treatment planning. In traditional practice. Prescribers are encouraged to view environments, psychiatrists often operate under BNF recommendations for escalations (e.g. every pressure to discharge early when the timeline 3 days or so) as, in most instances, representing for ‘improvement’ is in reality more protracted, a the ‘rapid’ end of the spec­trum (British Medical deficit they cover with dose escalation. In home Association 2102). or community contexts, however, pressure comes from ensuring that treatment is ‘adequate’, as C onclusions much to cover perceptions of risk as to manage The use of older antipsychotics is not inherently active symptomatology. more ‘difficult’ or more ‘risky’ than newer drugs. The intuitive but unsound principle underlying Perhaps the ‘difficulty’ with antipsychotics lies in rapid dose escalations is that response times can trying to dispel the myths of the past two decades – be shortened accordingly. Systematic review has that there is a group of these compounds inherently replicated early findings that greatest improvement ‘better’ than what came before. The only thing in psychotic symptoms in schizophrenia occurs inherent to antipsychotic drugs is that, as a class, during the first week or two of treatment (National they are all difficult to use – both for doctors who Institute of Mental Health Psychopharmacology prescribe them and for patients who take them. Service Center Collaborative Study Group 1964; Seeing antipsychotics as challenging therapeutic Agid 2003). However, in my experience this agents is the first step in acquiring the skills that reflects not fundamental improvement but non- utilising them to maximum effect demand and specific benefits in anxiety and general arousal, that should be part of every psychiatrist’s core removing some of the ‘drive’ fuelling psychotic competencies. symptomatology. There is experimental support for such a view (Johnstone 1979). This being the case, R eferences the first priority is to avoid rapid dose escalations Abhijnhan A, Adams CE, David A, et al (2007) Depot fluspirilene for during the first week or two of exposure, especially schizophrenia. Cochrane Database of Systematic Reviews issue 1: since this is when kinetic parameters are changing CD001718 (doi: 10.1002/14651858.CD001718.pub2). to those of repeat exposure, which themselves Agid O, Kapur S, Arenovich T, et al (2003) Delayed-onset hypothesis may facilitate tolerability. It is also important to of antipsychotic onset – a hypothesis tested and rejected. Archives of General Psychiatry 60: 1228–35. bear in mind that, pharmacologically, the largest Atkins M, Burgess A, Bottomley C, et al (1997) Chlorpromazine dose increment of all is the one from zero to any equivalents: a consensus of opinion for both clinical and research starting regime, no matter how modest. applications. Psychiatric Bulletin, 21: 224–6.

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MCQs 4 On the basis of a once-weekly dosing Link up the most appropriate drug option(s) above Select the single best option for each question stem schedule, pimozide has been found to be with the statements below associated with: 1 in psychotic states, is particularly useful for 1 Of the following, the longest half-life is a comparable maintenance effect to long-acting sedative properties (choose 3) held by: injectable risperidone 2 is most likely to be associated with a flupentixol b no tardive dyskinesia hyperprolactinaemia (choose 1) b fluspirilene c post-absorptive blood level peak (C ) delayed 3 is a moderate inhibitor of CYP2D6 (choose 2) c haloperidol max until day 4 4 is approved in the UK for short-term/adjunctive d pimozide d prolactin levels sustained over the 7-day cycle use in severe anxiety (choose 5) e zuclopenthixol. e significant weight loss. 5 is approved in the UK for use in depressive states (choose 1). 2 ‘Highly selective’ dopamine D2 antagonist EMI applies most accurately to: This question relates to both parts this article a flupentixol b haloperidol Theme: Antipsychotic therapeutics c pimozide Options d sulpiride a Chlorpromazine e zuclopenthixol. b Haloperidol c Flupentixol d Levomepromazine 3 QTc prolongation is a consequence of e Pericyazine blockade of: f Perphenazine a Ca 2 calcium channels v g Pimozide b GABA–chloride ionophore channels h Prochlorperazine c K calcium-activated potassium channels Ca i Promazine d I potassium channels Kr j Sulpiride e Na 1 sodium channels. v k Trifluoperazine l Zuclopenthixol

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