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Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 1 to 12 of 12. This is the beginning of the thread.
Posted by SLS on July 27, 2000, at 10:33:56
Does anyone know anything about the use of reserpine in the treatment of depression?
Thanks.
- Scott
Posted by Sunnely on July 28, 2000, at 0:39:09
In reply to Reserpine for treating depression ?, posted by SLS on July 27, 2000, at 10:33:56
> Does anyone know anything about the use of reserpine in the treatment of depression?
Reserpine is used primarily as an antihypertensive drug, although reports of its use in the treatment of psychosis date back to ancient Hindu Ayurvedic texts. Reserpine was used to treat psychosis before the introduction of antipsychotics in the 1950s.Once known for its role in causing depression, reserpine has been suggested as effective for depression when given in combination with tricyclic antidepressants. Several studies showed benefits from the use of reserpine and TCAs but more recent studies, however, have placed a question mark on these benefits.
Posted by Chris A. on July 28, 2000, at 18:59:04
In reply to Reserpine for treating depression ?, posted by SLS on July 27, 2000, at 10:33:56
Dear Scott,
Sorry you're feeling so lousy. My memory is returning in bits and I remember patients from my nursing days as getting very depressed on reserpine. Have you seen any research done on it for bipolar? Does it address mania/hypomania at all?My docs and consultants don't believe at all that any ADs are going to address my depression (other than a snippet of MAOI - currently seligiline 10 mg). They are of the strong opinion that anything that brings me up is going to initiate crashes into the depths. This makes some sense when you consider all of the intricate neurological feedback mechanisms, which those of us who are bipolar experience the effects of. We are just working on stabilization - hopefully at a level that is tolerable and functional. One of my consultants had suggested ziprasidone, which has finally been released (does anyone know what the reported incidence of TD is for it? My regular pDoc is thinking oxcarbazepine might be a good adjunct to the lamotrigine. I would like to get off the Klonopin. I'm sure it doesn't help my cognitive difficulties. We haven't decided whether a trip to Boston is worth the bother yet. We'll see how the next couple of months go.
We're heading for the hills for three days, so guess I'd better attend to details.
Blessings and Prayers, (don't really care if they're scientific or not)!
Chris A.
Posted by AndrewB on July 28, 2000, at 20:14:58
In reply to Re: Reserpine for treating depression ?, posted by Chris A. on July 28, 2000, at 18:59:04
Chris,
Is ziprasidone approved in the US and available in pharmacies? It seems like it might be as good or better than amisulpride for dysthymia. I remember a poster a long time ago on this board, who was in a ziprasidone trial, said it was a miraculous, I think that was the word used, med for her bipolar condition. Hope you find some kind of relief somewhere.
AndrewB
Posted by Chris A. on July 29, 2000, at 0:35:02
In reply to Chris: ziprasidone, posted by AndrewB on July 28, 2000, at 20:14:58
> Chris,
>
> Is ziprasidone approved in the US and available in pharmacies?It was my understanding that it's just been FDA approved. I would search the FDA site, but am trying to get out of town at the momment. If approved, it should be obtainable by any pharmacy. My concern is over any potential for aggravating TD. I am very sensitive and already have just a touch of it. Steven Dubovsky at U. Colo. was my consultant who thought it would be a good prospect.
About three days of no stress should be helpful for about anything.
Thanks,
Chris A.
Posted by AndrewB on July 29, 2000, at 9:54:33
In reply to Re: ziprasidone » AndrewB, posted by Chris A. on July 29, 2000, at 0:35:02
Due to ziprasidine's antagonism of the 5-HT2A receptors, it supposedly will not cuase TD. It is being investigated to treeat Tourette's actually.
Checked out the FDA site and no announcement of approval. But the site doesn't list events of the last couple of weeks or so, so maybe approval occurred in the interim.
Can anybody verify that it has approval?
AndrewB
Posted by SLS on July 29, 2000, at 10:39:48
In reply to Re: Reserpine for treating depression ?, posted by Sunnely on July 28, 2000, at 0:39:09
Dear Sunnely,
Thank you for your input.
Years ago, I saw some stuff written up in the late 1970s that reserpine was used as a pretreatment before beginning a tricyclic antidepressant. It was not taken concomitantly. I don't know the particulars of the procedure, however. Someone recently mentioned this treatment on Psycho-Babble, so I wonder if it is still used on occasion. He called it "kick-starting" an antidepressant and referred to its use with an MAO inhibitor.
I believe that reserpine prevents the uptake of neurotransmitter by synaptic storage vesicles. My question is, does reserpine simply bind to some transporter receptor reversibly or irreversibly, or does it actually destroy the vesicle?
I don't remember if a mechanism had been proposed for why reserpine pretreatment worked. Perhaps it encourages the formation of new vesicles. Maybe amine depletion leads to the activation of presynaptic feedback loops immediately prior to the initiation of other potentiation events produced by antidepressants. Any thoughts on this?
What are your impressions of the use of yohimbine as an adjunct to tricyclics or MAOIs?
Thanks.
- Scott
> > Does anyone know anything about the use of reserpine in the treatment of depression?
>
>
> Reserpine is used primarily as an antihypertensive drug, although reports of its use in the treatment of psychosis date back to ancient Hindu Ayurvedic texts. Reserpine was used to treat psychosis before the introduction of antipsychotics in the 1950s.
>
> Once known for its role in causing depression, reserpine has been suggested as effective for depression when given in combination with tricyclic antidepressants. Several studies showed benefits from the use of reserpine and TCAs but more recent studies, however, have placed a question mark on these benefits.
Posted by Cam W. on July 29, 2000, at 11:55:32
In reply to Re: Reserpine for treating depression ? » Sunnely, posted by SLS on July 29, 2000, at 10:39:48
Scott - If I remember correctly (no little feat, recently), I believe that reserpine depletes monoamine stores and this causes the emergence of depressive symptoms in those that are depressed or are prone to depression. Reserpine is contraindicated in those with depression or a history of depression. It has also been implicated in suicides of those with depression.
Can't remember much more about it right now. Hope this helps a bit. - Cam
Posted by KarenB on July 29, 2000, at 12:17:45
In reply to Re: ziprasidone » AndrewB, posted by Chris A. on July 29, 2000, at 0:35:02
Andrew,
You asked if ziprasidone (Zeldox) is now available in the US. I copied the following from the FDA site:
07-18-00, http://www.fda.gov/ohrms/dockets/ac/00/backgrd/3619b1.htm
Summary: Zeldox (ziprasidone hydrochloride capsules) NDA 20-825 The statements contained in
this document are those of the product's sponsor, not FDA, and FDA does not necessarily agree
with the sponsor's statements. FDA has not made a final determination about it.Does anyone know if there is any more recent info or approval? This looked like the most recent documentation I could find :(
Maybe the FDA board members don't own enough stock in the company yet? Not that I'm cynical or anything...
Karen
Posted by Sunnely on July 29, 2000, at 12:56:21
In reply to Re: ziprasidone- Chris, posted by AndrewB on July 29, 2000, at 9:54:33
> Can anybody verify that it has approval?
The Psychopharmacological Drugs Advisory Committee to the US FDA recently voted to recommend that the agency approve Pfizer's Zeldoz (ziprasidone) for the treatment of schizophrenia. Almost always the FDA goes along with the recommendation of the Advisory Committee, so Zeldoz should be out in the market fairly soon.
Pfizer and the FDA need to iron out some kinks, yet, particularly related to the drug's potential to cause an electrocardiogram abnormality termed "prolongation of the QT." When the QT is corrected for heart rate, it is termed "QTc." This ECG abnormality can lead to potentially serious heart rhythm irregularity called "torsades de pointes" which in turn can lead to an even more serious heart rhythm irregularity such as ventricular fibrillation and sudden cardiac death.
The FDA is more particularly cautious about approving drugs with potential to cause prolongation of QTc. Drugs known to cause this ECG abnormality such as Seldane and Hismanal (both nonsedating antihistamines), and Propulsid (for GERD), have been removed from the pharmacy shelves due to several reports of sudden cardiac deaths. (Over 100 sudden cardiac deaths linked to Seldane and Hismanal; about 80 deaths to Propulsid.)
Check with your physician or pharmacist regarding drug-drug interactions with Zeldox before taking it. It is possible that other psychotropic such as the antidepressants and nonpsychotropic drugs such as certain antibiotics may raise Zeldox's blood level. Also, it is possible that grapefruit juice may raise Zeldox's blood level (not sure about this). If you have a pre-existing heart condition, this drug may not be right for you. Whether ECG before and periodic ECG during treatment will be required while on Zeldox is not known, yet.
Posted by SLS on July 29, 2000, at 14:04:01
In reply to Re: ziprasidone- Chris, posted by Sunnely on July 29, 2000, at 12:56:21
According to Pfizer, ziprasidone is metabolized primarily by the CYP 3A4 enzyme, but it is not expected to produce major interactions with other drugs.
Sunnely and Cam - Is this an example of a substrate for an enzyme not being an inhibitor of it? Is the lack of enzyme inhibition a function of binding affinity? I don't know what Ki, Km, or Vmax represent.
- Scott
--------------------------------------------
1: Br J Clin Pharmacol 2000;49 Suppl 1:35S-42S Related Articles, Books
Identification of the major human liver cytochrome P450 isoform(s) responsible for the formation of the primary metabolites of ziprasidone and prediction of possible drug interactions.Prakash C, Kamel A, Cui D, Whalen RD, Miceli JJ, Tweedie D
Department of Drug Metabolism, Pfizer Central Research, Groton, CT 06340, USA.
AIMS: To identify the cytochrome P450 (CYP) isoform(s) responsible for the formation of the primary metabolite of ziprasidone (ziprasidone sulphoxide), to determine the kinetics of its formation and to predict possible drug interactions by investigating CYP isoform inhibition in an in vitro study. METHODS: In vitro metabolism of [14C]-ziprasidone was studied using human liver microsomes. The metabolites were identified using mass spectrometry. The kinetics of metabolite formation were determined using [14C]-ziprasidone (10-200 microM) over 5 min, and Km and Vmax were estimated from Lineweaver-Burk plots. IC50 values for the inhibition of specific probe substrates for CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4, by ziprasidone, risperidone and 9-hydroxyrisperidone were also determined using human liver microsomes from three subjects. Mean Ki values were calculated. RESULTS: Three CYP-mediated metabolites - ziprasidone sulphoxide, ziprasidone sulphone and oxindole acetic acid - were identified. The apparent Km and Vmax values for the formation of the major metabolite, ziprasidone sulphoxide (measured as the sum of sulphoxide and sulphone) were 235 microM and 1.14 nmol mg(-1) protein min(-1), respectively. Isoform-selective inhibitors and recombinant enzymes indicated that CYP3A4 is responsible for the formation of ziprasidone metabolites. Ziprasidone was not a substrate for the other isoforms studied. Similar in vitro inhibition of CYP2D6 (Ki 6.9-16 microM) and CYP3A4 (Ki 64-80 microM) was obtained with ziprasidone, risperidone and 9-hydroxyrisperidone. The in vivo free drug concentrations associated with clinically effective doses of ziprasidone are at least 1500-fold lower than the mean Ki for either CYP2D6 inhibition or CYP3A4 inhibition. CONCLUSIONS: Ziprasidone is predominantly metabolized by CYP3A4 in human liver microsomes and is not expected to mediate drug interactions with coadministered CYP substrates, at clinically effective doses.
PMID: 10771452, UI: 20235226
Posted by Sunnely on July 29, 2000, at 23:02:24
In reply to Re: ziprasidone- Chris, posted by SLS on July 29, 2000, at 14:04:01
> According to Pfizer, ziprasidone is metabolized primarily by the CYP 3A4 enzyme, but it is not expected to produce major interactions with other drugs.
Indeed, ziprasidone is predominantly metabolized by CYP3A4. It is therefore a "substrate" of this liver enzyme. You can therefore expect that the product information will include the following warning regarding drug-drug interactions with ziprasidone:
Drugs that either moderately or markedly inhibit the action of CYP3A4, slowing down the metabolism of ziprasidone consequently raising its blood levels (with potential for prolongation of QTc on ECG) are:
1. cimetidine (Tagamet); 2. Erythromycin; 3. troleandomycin (Tao); 4. the antifungals such as ketoconazole (Nizoral), itraconazole (Sporanox); 5. antidepressants such as Prozac and Luvox; 6. diltiazem (Cardizem), a calcium-channel blocker; 7. propoxyphene (Darvon); 8. amiodarone (Cordarone); 9. some of the drugs for HIV called protease inhibitors such as ritonavir (Norvir) and saquinavir (Fortovase, Invirase); and 10. grapefruit juice.
Drugs that are known to stimulate or induce the action of CYP3A4, hastening the metabolism of ziprasidone leading to decrease in its blood levels, and consequently losing its effectiveness are:
1. carbamazepine (Tegretol); 2. phenytoin (Dilantin); 3. phenobarbital; 4. primidone (Mysoline); 5. anti-TB drug, rifampin (Rifadin); 6. dexamethasone.
Ziprasidone itself has not been found, in in vitro studies, to either induce or inhibit the cytochrome enzymes.
A couple of advantages of ziprasidone over the other atypical antipsychotics are: 1. low propensity to cause weight gain, and 2. may have antidepressant and antianxiety effect due to its moderate inhibition of both norepinephrine and serotonin reuptake.
This is the end of the thread.
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