Traditional anti-psychotics have fallen out of fashion in the U.S., primarily thanks to the heavy promotion of pharmaceutical companies and their psychiatrist agents who dominate the American Psychiatric Association's panels on medication practices and well as pack the DSM-IV panels.  Yes, the field of academic psychiatry is highly corrupt.  While the traditional anti-psychotics do cause more tardive dyskinesia (TD) than atypicals do, they are much less expensive.  Many patients don't get TD from traditional anti-psychotics and of those who do, switching them to atypicals or giving them melatonin may resolve the problem.  The atypicals do have a slightly better record at treating psychosis, but the difference is small, and the studies are almost all biased in favor of the atypicals.  Most patients with schizophrenia will do fine on traditional anti-psychotics.

Patients at higher risk for tardive dyskinesia are the elderly.  Thus, it may be wise to avoid traditionals in these patients.  Also, thioridazine (Mellaril) has been discovered to cause a sizeable increase in the rate of sudden death due to irregular heart beats.  It should no longer be given under any circumstance.  Other traditional anti-psychotics, especially haloperidol, like virtually all of the aypticals, cause a smaller increase in the death rate with the impact primarily on the elderly.  Anti-psychotics may all increase heart disease and death in schizophrenics, but not treating causes an even higher death rate due to other causes.  Magnesium supplementation probably lowers the risk of heart disease.  In my opinion, all patients with schizophrenia should be given magnesium because they are at an elevated risk for developing diabetes, heart disease, and early death due to these.  

The most popular traditional anti-psychotics are: chlorpromazine (Thorazine)(1), thioridazine (Navane)(10), perphenazine (Trilafon)(16), haloperidol (Haldol)(60), and fluphenazine (Prolixin)(70) in their order of potency per milligram.  Patients with schizophrenia need 600-800 chlorpromazine equivalents to most rapidly recover from a psychotic relapse.  Higher doses are not harmful, but have never been proven to be of any benefit, despite a number of very high dose studies.  Most patients can be maintained in the 300-400 chlorpromazine equivalent range.  Based on these measures, the dosage of perphenazine used in CATIE appears on the low side.  Depot haloperidol decanoate costs $10 per month vs. $1200 per month for Risperdal Consta, the only atypical depot medication, for the most effective dosages.

The low potency chlorpromazine causes the most drowsiness and the least stiffness and pacing (extra-pyramidal) side-effects.  Prolixin is just the opposite with the others all intermediate roughly in proportion to their potency.  Chlorpromazine causes some weight gain while haloperidol and fluphenzaine cause very little.

The big advantage of the traditionals is that they are much less expensive than the atypicals.  The typical difference is $50 per month vs. $300-$400 per month. 

Atypicals Slightly Better than Haldol for Cognitive Improvement Although Difference May be Due to Benztropine: In a 1-year DB study of 414 patients with schizophrenia and schizoaffective disorder, measurements of executive function, learning and memory, processing speed, attention/vigilance, verbal working memory, verbal fluency, motor function, and visuospatial ability found the greatest improvement for olanzapine and risperidone  (p<0.01), compared to haloperidol, although haloperidol also showed clear improvement (p=0.04 for haloperidol) and the difference was not clinically significant. One-year double-blind study of the neurocognitive efficacy of olanzapine, risperidone, and haloperidol in schizophrenia. Keefe RS, et al. Duke University. Schizophr Res. 2005 Sep 30.  Ed: Since many of the haloperidol patients were on benztropine (Cogentin) for side-effects and since this causes cognitive impairment, the entire difference may have been a side-effect of benztropine.  Amantidine can be used to treat the same side-effects without cognitive impairment, but few American psychiatrists are even aware of the use of amantidine for this indication.

Perphenazine and Abilify Equally Effective for Treatment Resistant Schizophrenia: In a 6-week DB PC study of 300 schizophrenia patients who had failed to adequately improve after 4 to 6 weeks of open-label treatment with olanzapine or risperidone, aripiprazole (15-30 mg/day) did no better than perphenazine (8-64 mg/day) with 27% and 25% showing a >or = to 30% decrease in PANSS total score or a Clinical Global Impressions-Improvement score of 1 or 2. Perphenazine-treated patients had a higher incidence of extrapyramidal symptoms and a higher rate of elevated prolactin levels than aripiprazole (57.7% vs. 4.4%, p < .001). Improvements in quality of life considered to be clinically relevant (>or= 20% improvement in Quality of Life Scale score) occurred in 36% of the aripiprazole-treated patients and in 21% of those treated with perphenazine (p = .052). Aripiprazole for treatment-resistant schizophrenia: results of a multicenter, randomized, double-blind, comparison study versus perphenazine. Kane JM, et al. Albert Einstein College of Medicine. [email protected].  J Clin Psychiatry 2007 Feb;68(2):213-23. Ed: It appears that EPS side-effects may have been inadequately treated, making perphenazine appear at a disadvantage. Also, an elevated prolactin level is often a benign and asymptomatic finding. Abilify costs $392-553/month at doses used in this study vs. $92-260 for perphenazine at Walgreen prices. Perphenazine can be obtained for as little as $4 per month at Wal-Mart. Also, this study put perphenazine at a disadvantage since 8 mg is only one-quarter of the standard dose while Abilify 15 mg is a full standard dose.

Risperidone Did Somewhat Better than Haldol or Perphenazine: In an 8 week DB PC study of

Depot Perphenazine Best; Off Meds Associated with Increased Death Rate: In a study of a nationwide cohort of 2230 consecutive adults hospitalized in Finland for the first time because of schizophrenia or schizoaffective disorder, initial use of clozapine (adjusted relative risk 0.17), perphenazine depot (0.24), and olanzapine (0.35) were associated with the lowest rates of discontinuation for any reason when compared with oral haloperidol. During an average follow-up of 3.6 years, 4640 cases of rehospitalisation were recorded. Current use of perphenazine depot (0.32), olanzapine (0.54), and clozapine (0.64) were associated with the lowest risk of rehospitalisation. Use of haloperidol was associated with a poor outcome among women. Mortality was markedly raised in patients not taking antipsychotics (12.3) and the risk of suicide was high (37.4). Effectiveness of antipsychotic treatments in a nationwide cohort of patients in community care after first hospitalisation due to schizophrenia and schizoaffective disorder: observational follow-up study. Tijhonen J, et al. University of Kuopio, Finland. . Brit Med J 2006 Jul 29;333(7561):224.

CATIE Study Biased: In an 18-month DB study of 1493 patients with schizophrenia, olanzapine (7.5 to 30 mg per day), perphenazine (8 to 32 mg per day), quetiapine (200 to 800 mg per day), risperidone (1.5 to 6.0 mg per day) or ziprasidone (40 to 160 mg per day) were given. Discontinuation rates were olanzapine 64%, perphenazine 75%, quetiapine 82%, risperidone 74%, and ziprasidone 79%. The time to the discontinuation of treatment for any cause was significantly longer in the olanzapine group than in the quetiapine (P<0.001) or risperidone (P=0.002) group, but not in the perphenazine (P=0.021) or ziprasidone (P=0.028) group. The times to discontinuation because of intolerable side effects were similar among the groups, but the rates differed (P=0.04); olanzapine was associated with more discontinuation for weight gain or metabolic effects, and perphenazine was associated with more discontinuation for extrapyramidal effects. Olanzapine was associated with greater weight gain and increases in measures of glucose and lipid metabolism. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. Lieberman JA, et al. Columbia University. . New Eng J Med 2005 Sep 22;353(12):1209-23. Ed: Ziprasidone and perphenazine were handicapped by relatively lower doses. Also, it is likely that psychiatrists cared much less about weight gain than patients.  Weight gain would be highest with olanzapine, quetiapine, and risperidone in that order.  In addition, most psychiatrists undertreat EPS, which probably handicapped perphenazine.