Summer 2001 - IP; Psychopharmacology: 4+1=5: Atypical Neuroleptic Update

Dan Egli, Ph.D.

Editors’ Note: With psychologists increasingly collaborating with physicians and eventually likely to gain prescription privileges, we asked Dan Egli to write articles on medications. His columns will tap his knack for focusing on the practical implications of common and new psychotropic medications. We are delighted he has taken on the assignment.

The above mathematical equation summarizes the recent state of affairs in the atypical neuroleptic world. The FDA recently approved Pfizer’s atypical neuroleptic/antipsychotic ziprasidone. It will now be marketed as Geodon rather than Zeldox. The FDA and Pfizer agreed that Zeldox sounded too much like other currently available medications with zsounds to keep that name. Geodon becomes the fifth atypical neuroleptic (AN) to hit the U.S. market, following the introduction of clozapine (Clozaril), risperidone (Risperdal), olanzapine (Zyprexa), and quetiapine (Seroquel). It is likely to be indicated, as are the other AN’s for the treatment of schizophrenia and may have a double indication for both schizophrenia and schizoaffective disorder.

Like the other AN’s, Geodon is an SDA (serotonin and dopamine antagonist) and specifically has the highest 5HT2a/D2 receptor binding ratio. The practical import of this may be a lower risk of movement disorders (e.g. tardive dyskinesia [TD]) and possible increased efficacy for both positive and negative schizophrenic symptoms. The fact the Geodon is a modest SNRI (serotoninnorepinephrine reuptake inhibitor) as well may mean it will have antidepressant properties as well. It’s antimanic properties are unknown at this time. I mention this due to the fact that one of the AN’s (olanzapine) has formal FDAapproval for bipolar disorder as well as schizophrenia and one sometimes sees the offlabel use of the other AN’s in bipolar disorder patients.

Stahl (1999) suggests that eight benefits accrue from atypical antipsychotics that have 5HT2a/D2 antagonism (in contrast to the older typical neuroleptics with D2 antagonism alone), those being:

Fewer extrapyramidal side effects (EPS) than with haloperidol (Haldol),
Essentially no EPS,
Reduced incidence of TD,
Less likelihood of hyperprolactinemia than with haloperidol,
Essentially no increases in prolactin,
Better improvement of negative symptoms than with placebo,
Better improvement of negative symptoms than with haloperidol, and
Effective for symptoms that are refractory to treatment with conventional antipsychotics.

Ziprasidone fits all eight of the above criteria, and when marketed and used will, no doubt, capture a significant share of the AN market. Two other features of Geodon will enhance it’s marketability, those being it’s essential weightneutral (i.e. unlikely to cause weight gain) effect and it’s intramuscular (IM) formulation, something that will be useful in inpatient settings where rapid neuroleptization may be required. The IM formulation is neither a slowrelease nor a depot formulation. In clinical use it was effective within 2 hrs. in reducing agitation and aggression without causing profound sedation or movement disorders. Full approval of this formulation of Geodon is still pending in the U.S.

The biggest concern for the FDA before approving Geodon was its association with QTc prolongation. This cardiac sideeffect will lead to a lengthy warning in the package insert (P.I.) and product monograph (P.M.) about possible increased risks of this problem. The concern, in recent years has led some drugs to be withdrawn before being marketed (e.g. the atypical neuroleptic sertindole [Serlect]), some manufacturer’s to add a “black box” (i.e. bold letters that emphasize a serioius sideeffect) warning (e.g. thioridazine [Mellaril] and mesoridazine [Serentil]) and several existing medications to be totally withdrawn from the market altogether (e.g. terfenadine [Seldane/SeldaneD], astemizole [Hismanal], cisapride [Propulsid], and grepafloxacin [Raxar]).

Patients now starting on almost any of the AN’s, and this will certainly be the case with Geodon, will be screened for whether they would be at risk for developing QTc prolongation (risk factors being such things as gender, age, concomitant medications, cardiac disease, electrolyte imbalance, etc.), will be counseled about reporting sideeffects (e.g. lightheadedness, tachycardia, or diarrhea), and getting baseline and/or periodic ECG’s and serum K+ and Mg+ levels. Prolongation of the QTc interval can cause cardiac arrhythmias including the particularly serious one know as torsade de pointes, and sudden death. Before approving Geodon, the FDA required Pfizer to do additional testing with a particular focus on this issue and they were particularly concerned as to whether cytochrome P450 inhibitors in combination with Geodon caused increased QTc. Clinicians wanting more information on this issue can find helpful data at the following sources:

European Society of Cardiology (ESC) guidelines: www.escardio.org/scinfo/Guidelines/Haverkamp.pdf
Sudden Arrhythmia Death Syndromes Foundation (SADSF): an overview of long QT syndrome at www.sads.org (800)7867723.
The Georgetown Center for Education and Research Therapeutics (CERT): article “Drugs that Prolong the QT Interval and/or Induce Torsade de Pointes” at www.torsades.org

Geodon will be available in 20, 40, 60, and 80 mg. capsules and will be administered twice daily (b.i.d.). Its’ mean halflife is 6.6 hours. Typical daily doses in European trials were between 80160 mg/d. It will be recommended that it be taken with food to increase its bioavailability and no dosage adjustment appears necessary in geriatric populations although clinicians will be more prudent anyway and lower doses initially and work up as tolerated and given symptom resolution. Most clinicians will start patients off at 20 mg b.i.d. and work up from there.

In terms of drug-drug interactions, Geodon should obviously not be taken concomitantly with other drug that increase the QT interval. Contra-indications include psychotropics like thioridazine (Mellaril and pimozide (Orap) and non-psychotropics such as moxifloxacin (Avelox), sotalol (Betapace), and sparfloxacin (Zagam). Caution (but not contraindication) would be with such psychotropics as carbamazepine (Tegretol) and non-psychotropics as ketoconazole (Nizoral). Clinical trials would predict modest increases in ziprasidone plasma levels in conjunction with ketoconazole and modest decreases in ziprasidone plasma levels in conjunction with carbamazepine (inhibitors and inducers respectively). Ziprasidone is highly protein-bound (~99%) and does have two active metabolites (sulfoxide and sulfone) and there is no known (reliable) therapeutic plasma concentration. On a scale of 0-4 (0=none, 1=low, 2=moderate, 3=high, and 4=extremely high), ziprasidone would have the approximate following ratings:

Anticholinergic : 1
Weight Gain : 0/1
Orthostasis : 2
Sedation : 2
EPS : 2

One open-label, single-dose study (Sallee, et. al, 2000) showed ziprasidone to be well tolerated in subjects ages 7-17 who had Tourette’s syndrome. Children/teens had moderate-to-severe TS and were dosed in the usual mg/kg fashion. Serum lithium concentrations and renal clearance do not appear to be altered by ziprasidone (Apseloff, et. al., 2000). In general, studies so far seem to indicate a relatively benign P450 profile. Approximately 1/3 of a given dose of is metabolized the P450 enzyme 3A4. Clinical trials seem to suggest minimal to no interactions between ziprasidone and the benzodiazepine lorazepam (Ativan) and the beta-blocker propranolol (Inderal). I suspect that research will now also begin to focus on any possible anti-manic/anti-cycling properties of ziprasidone given that one study (Daniel, et. al., 1999) showed ziprasidone to be more effective for acute mania compared to placebo.

In summary, look for ziprasidone (Geodon) to make an impact in the AN market. Will it be cheaper? Probably not. Is it more effective? Probably not. Is it more preferential to use as a first-line AN? Probably not. It is generally more efficacious than currently available AN’s? Probably not. Is it less likely than existing AN’s to cause EPS or TD? Probably not. Can one tell which patients will be preferentially responsive to ziprasidone? No. Does it have an equally good or better P450 profile than existing AN’s? Probably. Is it less likely to cause problematic weight gain (and associated complications such as induced diabetes)? Probably. Does it have a slightly higher propensity to induce QTc prolongation? Probably.

Given this, I look for clinicians to quickly make use of this fifth atypical neuroleptic.

4+1=5

References

Apseloff, G., Mullet, D., Wilner, K.D., et. al. The effects of ziprasidone on steady-state lithium levels and renal clearance of lithium. British Journal of Clinical Pharmacology. 2000; 49 (Supplement 1):61S-64S).

Sallee, F.R., Miceli, J.J., Wilner, K.D. Pharmacokinetics of ziprasidone in children and adolescents with Tourette’s syndrome. European Neuropsychopharmacology. 2000; 10 (Supplement 3): S 289.

Stahl, Stephen M. Psychopharmacology of Antipsychotics. 1999, Martin Dunitz, Ltd., London, pp. 63, 87-88.

Dan Egli, Ph.D. has been teaching psychologists about psychopharmacology for more than a decade. He can be contacted at 454 Pine St., Suite 6 Eggs Williamsport, PA 17701-6200; phone 570-326-6111, E-mail: sixeggs@ptd.net.

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Continuing Education

	Psychopharmacology: 4+1=5: Atypical Neuroleptic Update/Dan Egli
	Exercise as a Therapeutic Modality: Adapting Psychological Treatments to Holistic Science and 21st Century Consumerism/Lori Huett

Psychopharmacology: 4+1=5: Atypical Neuroleptic Update

Dan Egli, Ph.D.

Editors’ Note: With psychologists increasingly collaborating with physicians and eventually likely to gain prescription privileges, we asked Dan Egli to write articles on medications. His columns will tap his knack for focusing on the practical implications of common and new psychotropic medications. We are delighted he has taken on the assignment.

The above mathematical equation summarizes the recent state of affairs in the atypical neuroleptic world. The FDA recently approved Pfizer’s atypical neuroleptic/antipsychotic ziprasidone. It will now be marketed as Geodon rather than Zeldox. The FDA and Pfizer agreed that Zeldox sounded too much like other currently available medications with zsounds to keep that name. Geodon becomes the fifth atypical neuroleptic (AN) to hit the U.S. market, following the introduction of clozapine (Clozaril), risperidone (Risperdal), olanzapine (Zyprexa), and quetiapine (Seroquel). It is likely to be indicated, as are the other AN’s for the treatment of schizophrenia and may have a double indication for both schizophrenia and schizoaffective disorder.

Like the other AN’s, Geodon is an SDA (serotonin and dopamine antagonist) and specifically has the highest 5HT2a/D2 receptor binding ratio. The practical import of this may be a lower risk of movement disorders (e.g. tardive dyskinesia [TD]) and possible increased efficacy for both positive and negative schizophrenic symptoms. The fact the Geodon is a modest SNRI (serotoninnorepinephrine reuptake inhibitor) as well may mean it will have antidepressant properties as well. It’s antimanic properties are unknown at this time. I mention this due to the fact that one of the AN’s (olanzapine) has formal FDAapproval for bipolar disorder as well as schizophrenia and one sometimes sees the offlabel use of the other AN’s in bipolar disorder patients.

Stahl (1999) suggests that eight benefits accrue from atypical antipsychotics that have 5HT2a/D2 antagonism (in contrast to the older typical neuroleptics with D2 antagonism alone), those being:

Fewer extrapyramidal side effects (EPS) than with haloperidol (Haldol),
Essentially no EPS,
Reduced incidence of TD,
Less likelihood of hyperprolactinemia than with haloperidol,
Essentially no increases in prolactin,
Better improvement of negative symptoms than with placebo,
Better improvement of negative symptoms than with haloperidol, and
Effective for symptoms that are refractory to treatment with conventional antipsychotics.

Ziprasidone fits all eight of the above criteria, and when marketed and used will, no doubt, capture a significant share of the AN market. Two other features of Geodon will enhance it’s marketability, those being it’s essential weightneutral (i.e. unlikely to cause weight gain) effect and it’s intramuscular (IM) formulation, something that will be useful in inpatient settings where rapid neuroleptization may be required. The IM formulation is neither a slowrelease nor a depot formulation. In clinical use it was effective within 2 hrs. in reducing agitation and aggression without causing profound sedation or movement disorders. Full approval of this formulation of Geodon is still pending in the U.S.

The biggest concern for the FDA before approving Geodon was its association with QTc prolongation. This cardiac sideeffect will lead to a lengthy warning in the package insert (P.I.) and product monograph (P.M.) about possible increased risks of this problem. The concern, in recent years has led some drugs to be withdrawn before being marketed (e.g. the atypical neuroleptic sertindole [Serlect]), some manufacturer’s to add a “black box” (i.e. bold letters that emphasize a serioius sideeffect) warning (e.g. thioridazine [Mellaril] and mesoridazine [Serentil]) and several existing medications to be totally withdrawn from the market altogether (e.g. terfenadine [Seldane/SeldaneD], astemizole [Hismanal], cisapride [Propulsid], and grepafloxacin [Raxar]).

Patients now starting on almost any of the AN’s, and this will certainly be the case with Geodon, will be screened for whether they would be at risk for developing QTc prolongation (risk factors being such things as gender, age, concomitant medications, cardiac disease, electrolyte imbalance, etc.), will be counseled about reporting sideeffects (e.g. lightheadedness, tachycardia, or diarrhea), and getting baseline and/or periodic ECG’s and serum K+ and Mg+ levels. Prolongation of the QTc interval can cause cardiac arrhythmias including the particularly serious one know as torsade de pointes, and sudden death. Before approving Geodon, the FDA required Pfizer to do additional testing with a particular focus on this issue and they were particularly concerned as to whether cytochrome P450 inhibitors in combination with Geodon caused increased QTc. Clinicians wanting more information on this issue can find helpful data at the following sources:

European Society of Cardiology (ESC) guidelines: www.escardio.org/scinfo/Guidelines/Haverkamp.pdf
Sudden Arrhythmia Death Syndromes Foundation (SADSF): an overview of long QT syndrome at www.sads.org (800)7867723.
The Georgetown Center for Education and Research Therapeutics (CERT): article “Drugs that Prolong the QT Interval and/or Induce Torsade de Pointes” at www.torsades.org

Geodon will be available in 20, 40, 60, and 80 mg. capsules and will be administered twice daily (b.i.d.). Its’ mean halflife is 6.6 hours. Typical daily doses in European trials were between 80160 mg/d. It will be recommended that it be taken with food to increase its bioavailability and no dosage adjustment appears necessary in geriatric populations although clinicians will be more prudent anyway and lower doses initially and work up as tolerated and given symptom resolution. Most clinicians will start patients off at 20 mg b.i.d. and work up from there.

In terms of drug-drug interactions, Geodon should obviously not be taken concomitantly with other drug that increase the QT interval. Contra-indications include psychotropics like thioridazine (Mellaril and pimozide (Orap) and non-psychotropics such as moxifloxacin (Avelox), sotalol (Betapace), and sparfloxacin (Zagam). Caution (but not contraindication) would be with such psychotropics as carbamazepine (Tegretol) and non-psychotropics as ketoconazole (Nizoral). Clinical trials would predict modest increases in ziprasidone plasma levels in conjunction with ketoconazole and modest decreases in ziprasidone plasma levels in conjunction with carbamazepine (inhibitors and inducers respectively). Ziprasidone is highly protein-bound (~99%) and does have two active metabolites (sulfoxide and sulfone) and there is no known (reliable) therapeutic plasma concentration. On a scale of 0-4 (0=none, 1=low, 2=moderate, 3=high, and 4=extremely high), ziprasidone would have the approximate following ratings:

Anticholinergic : 1
Weight Gain : 0/1
Orthostasis : 2
Sedation : 2
EPS : 2

One open-label, single-dose study (Sallee, et. al, 2000) showed ziprasidone to be well tolerated in subjects ages 7-17 who had Tourette’s syndrome. Children/teens had moderate-to-severe TS and were dosed in the usual mg/kg fashion. Serum lithium concentrations and renal clearance do not appear to be altered by ziprasidone (Apseloff, et. al., 2000). In general, studies so far seem to indicate a relatively benign P450 profile. Approximately 1/3 of a given dose of is metabolized the P450 enzyme 3A4. Clinical trials seem to suggest minimal to no interactions between ziprasidone and the benzodiazepine lorazepam (Ativan) and the beta-blocker propranolol (Inderal). I suspect that research will now also begin to focus on any possible anti-manic/anti-cycling properties of ziprasidone given that one study (Daniel, et. al., 1999) showed ziprasidone to be more effective for acute mania compared to placebo.

In summary, look for ziprasidone (Geodon) to make an impact in the AN market. Will it be cheaper? Probably not. Is it more effective? Probably not. Is it more preferential to use as a first-line AN? Probably not. It is generally more efficacious than currently available AN’s? Probably not. Is it less likely than existing AN’s to cause EPS or TD? Probably not. Can one tell which patients will be preferentially responsive to ziprasidone? No. Does it have an equally good or better P450 profile than existing AN’s? Probably. Is it less likely to cause problematic weight gain (and associated complications such as induced diabetes)? Probably. Does it have a slightly higher propensity to induce QTc prolongation? Probably.

Given this, I look for clinicians to quickly make use of this fifth atypical neuroleptic.

4+1=5

References

Apseloff, G., Mullet, D., Wilner, K.D., et. al. The effects of ziprasidone on steady-state lithium levels and renal clearance of lithium. British Journal of Clinical Pharmacology. 2000; 49 (Supplement 1):61S-64S).

Sallee, F.R., Miceli, J.J., Wilner, K.D. Pharmacokinetics of ziprasidone in children and adolescents with Tourette’s syndrome. European Neuropsychopharmacology. 2000; 10 (Supplement 3): S 289.

Stahl, Stephen M. Psychopharmacology of Antipsychotics. 1999, Martin Dunitz, Ltd., London, pp. 63, 87-88.

Dan Egli, Ph.D. has been teaching psychologists about psychopharmacology for more than a decade. He can be contacted at 454 Pine St., Suite 6 Eggs Williamsport, PA 17701-6200; phone 570-326-6111, E-mail: sixeggs@ptd.net.

Discuss this and other articles at the IP Chat Discussion Board

Return to Top