Those of us who completed residency anytime during the last 10 years were indoctrinated against the use of conventional neuroleptics because of their array of side effects, particularly extrapyramidal syndromes (EPS) and tardive dyskinesia (TD).

This was good education, as long as the atypicals continued to maintain their promise of being more effective with minimal side effects. But a host of findings recently have called the superiority of atypicals into serious question, culminating with the release of Phase 1 results of the CATIE trial (see article this issue), in which Trilafon (perphenazine) was as effective as the atypicals and caused fewer side effects than many. Trilafon-treated patients had identical AIMS (Abnormal Involuntary Movement Scale) scores as those on atypicals, calling into question the dogma that typicals cause moreTD. However, keep in mind that patients with pre-existing TD were not allowed to be randomized to the Trilafon group, surely improving Trilafon’s apparent AIMS profile.

Let’s begin our reacquaintance with typical antipsychotics by revisiting the issue of TD. A recent review looked at the whether there really is a lower risk of TD with second generation antipsychotics (SGAs, also knows as “atypicals”) compared to conventional neuroleptics (Am J Psychiatry 2004; 161:414-425). They found that the average annual incidence of TD in patients on SGAs (including Risperdal, Zyprexa, Seroquel, Geodon, and amisulpride) was 0.8% for adults, as opposed to 5.4% for Haldol, the standard comparator. However, they also found that in elderly populations, SGAs lead to a 5.4% annual incidence of TD—identical to Haldol’s TD risk in the elderly. The authors also point out that when SGAs are compared to Haldol in most studies, Haldol is dosed quite high—between 10 and 15 mg QD.

Haldol, being a high potency neuroleptic, may be the typical antipsychotic most likely to lead to TD. It’s difficult to get a handle on which of the typical neuroleptics are least likely to lead to TD, because few comparative studies have been done. One of the few we found compared patients treated with Haldol (n=68) to those treated with Mellaril (thioridazine; n=39). The Haldol group had a higher one-year cumulative incidence of TD than the thioridazine group (30.3 % vs. 9.3 %--in Arch Gen Psych 1995; 52:756-765).

Ultimately, the fact remains that for our non-elderly patients, putting them on typical antipsychotics increases their risk of TD substantially; choosing lower doses and lower potency agents may decrease this risk. Nonetheless, typical medications have some advantages, including low cost, minimal weight gain and fewer lipid problems (though this is not as true for the low potency meds, such as Mellaril and Thorazine), and a long track record of efficacy.

What about the supposed advantage of atypicals for the negative symptoms of schizophrenia, such as paucity of thought content, lack of motivation? There are nearly as many opinions about this controversial topic as there are psychiatrists.  One contingent (see for example,  BMJ 2000;321:1371–6) argues that the reason for the apparent advantage of atypicals is that they are usually compared with unreasonably high doses of typicals, and this is generally Haldol.  We all know that when Haldol is dosed too high, the result is often the slowed movement (and slowed mentation) of neuroleptic-induced Parkinsonism, which can be confused with negative symptoms.  Others have interpreted the studies differently, and argue that atypicals are clearly more effective for negative symptoms than typicals (see Arch Gen Psychiatry:  2003;60:553-564.)

At any rate, here are a few of the typical antipsychotics that have recently gained airplay, along with accompanying pearls should you be tempted to use them.

Haldol (haloperidol). The original high potency neuroleptic. Few psychiatrists prescribe it these days because of the high risk of EPS and akathisia. Sure, you can get by with Haldol if you pre-treat with Cogentin, and it doesn’t cause the weight gain of atypicals, but it has become the poster child of TD and no one wants to stay on Cogentin for the rest of their life if they can avoid it.

Trilafon (perphenazine). As a result of CATIE, Trilafon has become the darling of typicals. It offers a nice package: minimal weight gain compared to some atypicals, hypercholesterolemia, or hyperprolactinemia; it’s rarely over-stimulating (unlike, say, Abilify); and it’s extremely cheap. It’s often used off-label as a non-addictive anxiolytic, much as Mellaril was until its black box warning made it almost obsolete.

Mellaril (thrioridazine). Until quite recently, many of us used low dose Mellaril as a cheap and non-addictive tranquilizer. At 25 mg QD or BID prn anxiety, it was unlikely to cause TD. But in 2000 the FDA announced that it had reviewed data on the effects of Mellaril on QT intervals and proclaimed that it was too risky to use as a first-line agent. According to FDA guidelines, you should use Mellaril only if other antipsychotics fail, you should get a baseline EKG and potassium level, you shouldn’t co-administer it with certain drugs (including Luvox), and you shouldn’t give it to poor metabolizers of drugs dependent on P450-2D6 liver enzymes. While some are skeptical that Mellaril is really this dangerous, given 50 years of largely uneventful clinical use, psychiatrists uncomfortable with certified letters from law offices would be well-advised to toss Mellaril from their tool box.

Thorazine (chlorpromazine). This low-potency, sedating antipsychotic has replaced Mellaril as the go-to typical for low-dose, non-addictive tranquilization. Of course, most psychiatrists have been using 25 mg "dosettes" of Seroquel for this purpose, but switching to Thorazine at the same dose is much less taxing on our country’s health care budget.

Moban (molindone). There’s a buzz in the community that Moban is better tolerated than most typical antipsychotics. A recent Cochrane review looked at every relevant double-blind study ever conducted (13 studies met their criteria) and found that, indeed, Moban causes less weight gain, and possibly even some weight loss. However, it is no more effective and causes the same pattern of EPS as Haldol, Mellaril, and Thorazine, the drugs with which it was most commonly compared (Cochrane Database, 2005, vol. 4).

Loxapine (loxitane). Because its molecular structure is similar to clozapine, some have speculated that Loxapine has some degree of “atypicality” in terms of causing fewer movement disorders than other typical antipsychotics, but, alas, the Cochrane team crunched all the Loxapine numbers and found that it has the same side effect profile and efficacy as other typicals in double blind trials (Cochrane Database, 2005, vol. 4).

TCPR Verdict:
Judicious use of typicals is back in vogue.