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Suitable doses of typical APs..... Haldol » SLS

Posted by ed_uk on June 4, 2005, at 15:19:47

In reply to Re: mellaril to zyprexa equivilancy » ed_uk, posted by SLS on June 4, 2005, at 13:32:12

Hi Scott,

>There are fewer of us who use them to treat schizoid disorders and affective psychoses.

That's true but most p-babblers take atypical APs eg. for insomnia etc. In my post, I was specifically referring to typical neuroleptics.

>Trust me, for these latter people, the dosages advocated in the PDR or in general practice is not excessive, but necessary.

I think pdocs have a tendency to increase the dose before they've given the low dose chance to work. In the treatment of schizophrenia, an AP can take several weeks to have a good effect..... docs may increase the dose every few days in some cases.

Haloperidol (Haldol) in particular has often been prescribed at very high doses. 30mg/day was not unusual and doses of up to 200mg have been prescribed. The problem is, once someone is on a very high dose, it might be difficult to reduce it. Haloperidol, like most typical APs, is a potent D2 antagonist. The dose needs to be carefully titrated in order to optimise efficacy and minimise adverse effect. High doses (of typical APs) are useful for some patients (eg those who have low plasma concentrations on low doses) but in general, high doses of typical APs frequently produce severe/disturbing side effects and may not be any more effective than low doses.

*****2-3mg/day haloperidol (Haldol) is claimed to be 'equivalent' to 75-100mg thioridazine (Mellaril).

Here's some interesting stuff................

J Psychopharmacol. 2001 Dec;15(4):251-5.

Determining the optimal dose of haloperidol in first-episode psychosis.

Oosthuizen P, Emsley RA, Turner J, Keyter N.

Department of Psychiatry, University of Stellenbosch, Cape Town, South Africa. pieto@samedical.co.za

Uncertainty exists as to the most appropriate dose of haloperidol in first-episode psychosis. This study set out to determine whether ultra-low doses of haloperidol could successfully treat patients with first-episode psychosis. Thirty-five patients with a first episode of psychosis were treated with haloperidol in an open label, fixed protocol over a 12-week period with doses restricted to 1 mg per day for the first 4 weeks. Twenty-nine (83%) remained on haloperidol after 12 weeks at a mean dose of 1.78 mg per day, 16 (55%) had stabilized on 1 mg/day or less. The mean percentage reduction in Positive and Negative Symptom Scale score between baseline and 6 and 12 weeks was 30.3% (SD 20.9%) and 41.4% (SD 16.6%), respectively. There were no significant differences in mean extrapyramidal symptom ratings between baseline and 12 weeks. Ultra-low doses of haloperidol are effective and well tolerated in first-episode psychosis. Initial doses should be maintained for a sufficient period of time to allow for the medication to take full effect.

................................................................................................................................................

Even very low doses of haloperidol produce a high level of D2 occupancy.....

Am J Psychiatry. 2003 Feb;160(2):303-9.

Subjective experience and D2 receptor occupancy in patients with recent-onset schizophrenia treated with low-dose olanzapine or haloperidol: a randomized, double-blind study.

de Haan L, van Bruggen M, Lavalaye J, Booij J, Dingemans PM, Linszen D.

Academic Medical Center, University of Amsterdam Department of Psychiatry, The Netherlands. l.dehaan@amc.uva.nl

OBJECTIVE: The authors tested the hypothesis that a dopamine D(2) receptor occupancy level between 60% and 70% in patients with recent-onset schizophrenia would result in optimal subjective experience. In addition, they sought preliminary evidence on whether subjective experience is better with low-dose olanzapine than with low-dose haloperidol. METHOD: Subjects (N=24) who met DSM-IV criteria for schizophrenia were randomly assigned to 6 weeks of double-blind treatment with either olanzapine, 7.5 mg/day, or haloperidol, 2.5 mg/day. Subjective experience, psychopathology, and extrapyramidal symptoms were assessed at baseline and at endpoint. After 6 weeks, D(2) receptor occupancy was assessed with [(123)I]iodobenzamide single photon emission computed tomography. RESULTS: The two study groups were similar at baseline. After 6 weeks, patients receiving olanzapine had a significantly lower mean dopamine D(2) receptor occupancy (51.0%, range=36%-67%) than those given haloperidol (65.5%, range=45%-75%). Receptor occupancy between 60% and 70% was associated with optimal subjective experience, and subjective experience improved significantly in the haloperidol group. CONCLUSIONS: A level of D(2) receptor occupancy between 60% and 70% is optimal for subjective experience of patients with recent-onset schizophrenia. Substantial interindividual variation in D(2) receptor occupancy was seen at fixed low-dose levels of olanzapine and haloperidol. Olanzapine, 7.5 mg/day, showed no superior subjective response over haloperidol, 2.5 mg/day. Olanzapine may need to be dosed higher than 7.5 mg/day for most patients with recent-onset schizophrenia, and haloperidol needs to be individually titrated in the very low dose range to reach optimal occupancy.

................................................................................................................

Am J Psychiatry. 1996 Jul;153(7):948-50.

High levels of dopamine D2 receptor occupancy with low-dose haloperidol treatment: a PET study.

Kapur S, Remington G, Jones C, Wilson A, DaSilva J, Houle S, Zipursky R.

PET Centre, Clarke Institute of Psychiatry, Toronto, Ont., Canada. kapur@clarke-inst.on.ca

OBJECTIVE: The purpose of this study was to determine the dopamine D2 receptor occupancy induced by low-dose haloperidol treatment in a prospective trial. METHOD: Seven patients with schizophrenia were treated with 2 mg/day of haloperidol for 2 weeks, and D2 receptor occupancy was measured by [11C]raclopride and positron emission tomography. RESULTS: The patients showed high levels of D2 occupancy (53%-74%); five of them showed substantial clinical improvement, and none showed important side effects. CONCLUSIONS: The findings demonstrate that low doses of haloperidol induce D2 receptor occupancies that are in the putative therapeutic range. In combination with recent empirical trials, these findings should encourage clinicians to initiate treatment of psychotic episodes with low (2-4 mg haloperidol equivalent) doses of typical neuroleptics, particularly for first-episode patients.

...................................................................................................................

Careful titration of the dose may be very important to minimise side effects by avoiding excessive D2 occupancy......................

Am J Psychiatry. 2000 Apr;157(4):514-20.

Relationship between dopamine D(2) occupancy, clinical response, and side effects: a double-blind PET study of first-episode schizophrenia.

Kapur S, Zipursky R, Jones C, Remington G, Houle S.

Department of Psychiatry, University of Toronto, ON, Canada.

OBJECTIVE: Since all antipsychotics block dopamine D(2) receptors, the authors investigated how well D(2) receptor occupancy in vivo predicts clinical response, extrapyramidal side effects, and hyperprolactinemia. METHOD: In a double-blind study, 22 patients with first-episode schizophrenia were randomly assigned to 1.0 or 2. 5 mg/day of haloperidol. After 2 weeks of treatment, D(2) receptor occupancy was determined with [(11)C]raclopride and positron emission tomography, and clinical response, extrapyramidal side effects, and prolactin levels were measured. Patients who showed adequate responses continued taking their initial doses, those who did not respond had their doses increased to 5.0 mg/day, and evaluations were repeated at 4 weeks for all patients. RESULTS: The patients showed a wide range of D(2) occupancy (38%-87%). The degree of receptor occupancy predicted clinical improvement, hyperprolactinemia, and extrapyramidal side effects.

*****The likelihood of clinical response, hyperprolactinemia, and extrapyramidal side effects increased significantly as D(2) occupancy exceeded 65%, 72%, and 78%, respectively.*****

CONCLUSIONS: The study confirms that D(2) occupancy is an important mediator of response and side effects in antipsychotic treatment. The data are consistent with a "target and trigger" hypothesis of antipsychotic action, i.e., that the D(2) receptor specificity of antipsychotics permits them to target discrete neurons and that their antagonist properties trigger within those neurons intracellular changes that ultimately beget antipsychotic response. While limited to haloperidol, the relationship between D(2) occupancy and side effects in this study helps explain many of the observed clinical differences between typical and atypical antipsychotics.

Low doses of haloperidol can be an effective treatment for psychosis in some patients..........................................................

Int J Neuropsychopharmacol. 2004 Jun;7(2):125-31. Epub 2004 Mar 5. Related Articles, Links

A randomized, controlled comparison of the efficacy and tolerability of low and high doses of haloperidol in the treatment of first-episode psychosis.

Oosthuizen P, Emsley R, Jadri Turner H, Keyter N.

Department of Psychiatry, University of Stellenbosch, Cape Town, South Africa. pieto@sun.ac.za

While haloperidol is still widely used in the treatment of psychoses, the optimal daily dose remains a topic of controversy, particularly in first-episode psychosis. Previous studies have suggested that doses as low as 2 mg/d may be effective, whereas others have indicated superiority for higher over lower doses. This double-blinded, randomized controlled study compared the efficacy and tolerability of 2 vs. 8 mg/d of haloperidol over 6 wk in 40 subjects with first-episode psychosis. Both treatments were equally effective in reducing the PANSS Total and subscale scores. The low dose of haloperidol was better tolerated, with fewer extrapyramidal side-effects, less frequent use of anticholinergic medication and smaller elevations in prolactin levels. Using a low dose of haloperidol is at least as effective as, and better tolerated than a high dose of haloperidol in the treatment of first-episode psychosis.

......................................................................

A Cochrane review said.................

'Haloperidol dose for the acute phase of schizophrenia.'

'Using low doses (>3-7.5mg/day) did not clearly result in loss of efficacy (no clinically important improvement in global state, versus >7.5-15mg/day n=48, 1 RCT, RR 1.09 CI 0.7 to 1.8; versus >15-35mg/day n=81, 2 RCTs, 0.95 CI 0.8 to 1.2).

Doses of haloperidol in the range of >3-7.5 mg/day had a lower rate of development of clinically significant extrapyramidal adverse effects than higher doses (clinically significant extrapyramidal adverse effects, versus >7.5-15mg/day n=64, 2 RCTs, RR 0.12 CI 0.01 to 2.1; versus >15-35mg/day n=144, 3 RCTs RR 0.59 CI 0.5 to 0.8, NNH 3 CI 2 to 6; versus >35mg/day n=86, 2 RCTs, RR 0.70 CI 0.5 to 1.1).'

'It would be understandable, however, if clinicians were cautious in prescribing doses in excess of 7.5 mg/day of haloperidol to a person with uncomplicated acute schizophrenia, and if people with schizophrenia were equally reticent to take greater doses.'

.................................................................

CNS Drugs. 2001;15(9):671-8.

Choosing the right dose of antipsychotics in schizophrenia: lessons from neuroimaging studies.

Tauscher J, Kapur S.

Schizophrenia-PET Program, Centre for Addiction and Mental Health, University of Toronto, Toronto, Ontario, Canada. Jtauscher@camhpet.on.ca

Despite vast clinical experience with antipsychotics, there is no broad consensus on the doses of these substances that should be administered. Currently, most antipsychotics are administered empirically according to clinical dose-finding studies, in which arbitrarily selected doses were tested to find the "most efficient" dose range in a patient population, with no regard for the molecular effects of the tested drug. Brain imaging studies using nuclear medical techniques, such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), can now provide a rationale for doses, directly derived from the central effects of the drugs on neurotransmitter receptors measured in vivo. PET results indicate that occupancy of at least 65% of dopamine D(2) receptors is needed for clinical response to antipsychotics, and that occupancy rates exceeding 72 and 78% are associated with a high risk for elevation of prolactin levels and motor adverse effects, respectively. For example, clinical studies with haloperidol do not point to an advantage of dosages exceeding 5 mg/day. The relevance of D(2) receptor occupancy for drug administration is also borne out by studies relating the effects of antipsychotics to their D(2) receptor occupancy in relevant animal models. Taken together, neuroimaging and clinical studies, as well as animal models, provide a rationale for the use of relatively low doses of typical antipsychotics and equivalent doses of novel antipsychotics. The lower risk of adverse effects with appropriate doses of antipsychotics may further enhance compliance and outcome. This seems to be particularly important in individuals experiencing a first episode of schizophrenia, as they appear to be especially responsive to pharmacotherapy and quite sensitive to adverse effects.

....................................................................

****75-100mg thioridazine is claimed to be 'equivalent' to about 100mg chlorpromazine (Thorazine).

'What is the best maintenance dose of neuroleptics in schizophrenia?'

'..........Most long-term studies involved patients diagnosed as chronic schizophrenics and used phenothiazines; responses, dose requirements, and probably diagnosis were highly heterogeneous. Data from controlled studies permitting estimates of the equivalent dose of chlorpromazine to be plotted vs. reduction of relapse rates revealed no significant dose effect between 100 and over 2,000 (median = 310) mg/kg day, no mean difference in outcome at doses above vs. below 310 mg..........'

Kind regards,
Ed.


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URL: http://www.dr-bob.org/babble/20050601/msgs/507643.html