![[dr. bob]](/dr-bob-sm.gif)
Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 6 to 30 of 37. Go back in thread:
Posted by Quintal on January 20, 2007, at 0:02:44
In reply to Re: Zoloft and dopamine reuptake inhibition, posted by halcyondaze on January 19, 2007, at 21:44:16
__________________________________________________
Using radioligand binding assays, we determined the equilibrium dissociation constants (KD's) for 37 antidepressants, three of their metabolites (desmethylcitalopram, desmethylsertraline, and norfluoxetine), some mood stabilizers, and assorted other compounds (some antiepileptics, Ca2+ channel antagonists, benzodiazepines, psychostimulants, antihistamines, and monoamines) for the human serotonin, norepinephrine, and dopamine transporters. Among the compounds that we tested, mazindol was the most potent at the human norepinephrine and dopamine transporters with KD's of 0.45 +/- 0.03 nM and 8.1 +/- 0.4 nM, respectively. Sertraline (KD = 25 +/- 2 nM) and nomifensine (56 +/- 3 nM) were the two most potent antidepressants at the human dopamine transporter. We showed significant correlations for antidepressant affinities at binding to serotonin (R = 0.93), norepinephrine (R = 0.97), and dopamine (R = 0.87) transporters in comparison to their respective values for inhibiting uptake of monoamines into rat brain synaptosomes.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9537821&dopt=Abstract
__________________________________________________
http://www.preskorn.com/columns/9907.htmlhttp://www.preskorn.com/books/ssri_s3.html
So it would seem sertraline is one of the most potent SDRIs by far among the newer antidepressants?
Yet:
__________________________________________________"In Table 3.3, results are shown for the inhibition of the dopamine uptake pump. None of the TCAs or the SSRIs have substantial action on this neurotransmitter pump. Although sertraline is consistently the most potent, it is still 100 times less potent in terms of inhibiting the dopamine versus the serotonin uptake pump. That means the physician would have to increase the dose (ie, the concentration) of sertraline 100 times higher than that needed to inhibit the serotonin uptake pump before a comparable effect would be achieved on the dopamine uptake pump. Thus, the ratios shown in the bottom of Table 3.3 can be misleading if not viewed within the context of the actual affinity of the drug for a secondary SOA relative to its affinity for its primary SOA and relative to the clinically relevant concentration needed to produce the desired clinical effect. Recall that citalopram and fluoxetine are marketed as racemates (see Section 2). The values shown in the above tables for uptake inhibition are for the racemates of these two SSRIs. Table 3.4 shows the value for the individual enantiomers of each of these SSRIs and their major metabolite."
__________________________________________________And this wonderful little table:
__________________________________________________TABLE 3.6 — Pharmacologic Properties of Antidepressants and Possible Clinical Consequences
Property Consequences
Blockade of histamine (H-1and H-2) receptors: Sedation, drowsiness; potentiation of central depressant drugs; weight gain
Blockade of muscarinic acetylcholine receptors: Dry mouth, blurred vision, sinus tachycardia, constipation, urinary retention, memory impairment
Blockade of norepinephrine uptake at nerve endings: Antidepressant efficacy (?); tremors, jitteriness; tachycardia; diaphoresis; blockade of the antihypertensive effects of guanethidine; augmentation of pressor effects of sympathomimetic amines; erectile and ejaculatory dysfunction
Blockade of serotonin uptake at nerve endings: Antidepressant efficacy (?); sexual dysfunction; nausea, vomiting, diarrhea; anorexia; increase or decrease in anxiety (dose-dependent); asthenia (tiredness); insomnia; extrapyramidal side effects; interactions with L-tryptophan, monoamine oxidase inhibitors, fenfluramine, and occasionally lithium
Blockade of serotonin-2 (5-HT2) receptors: Antidepressant efficacy (?), ejaculatory dysfunction, hypotension, alleviation of migraine headaches, decrease in anxiety (?), decrease motor restlessness (?)
Blockade of a1-adrenergic receptors: Postural hypotension, dizziness which predisposes to falls possibly resulting in broken bones and subdural hematomas, potentiation of antihypertensive drugs
Blockade of a2-adrenergic receptors: Priapism; blockade of the antihypertensive effects of clonidine, a-methyldopa, guanabenz, guanfacine
Blockade of fast sodium channels: Slow repolarization, delay intracardiac conduction, reduce some arrhythmias at low concentrations, cause arrhythmias, seizures at high concentrations
__________________________________________________
I wonder if taking sertraline with tianeptine would reduce the SSRI effect making it more tolerable at higher doses, enabling a stronger DA reuptake effect?Q
Posted by iforgotmypassword on January 20, 2007, at 2:16:41
In reply to Re: Zoloft and dopamine reuptake inhibition » halcyondaze, posted by Quintal on January 20, 2007, at 0:02:44
Posted by Klavot on January 20, 2007, at 2:53:48
In reply to Re: Zoloft and dopamine reuptake inhibition » halcyondaze, posted by Quintal on January 20, 2007, at 0:02:44
I too have read that Zoloft has substantial dopamine reuptake inhibition properties. Strange though, the package insert states that
"Sertraline has only weak effects on neuronal reuptake of norepinephrine and dopamine."
(see e.g. http://home.intekom.com/pharm/pfizer/zoloft-t.html ).
You'd think that if Zoloft *did* inhibit dopamine reuptake significantly, Pfizer would promote it as such, since dopamine reuptake is supposed to be good.
I might add that the precise mechanism of action of Wellbutrin has not been fully elucidated. Its dopaminergic effect may entail more than just simple dopamine reuptake inhibition. So indeed, Zoloft may inhibit dopamine reuptake more than Wellbutrin, but that does not mean that it has a greater dopaminergic effect.
Finally, dopamine isn't quite the miracle amine that it is often portrayed as. Studies have shown that dopamine regulates *desire* rather than *pleasure*, see e.g.
http://en.wikipedia.org/wiki/Dopamine
That dopaminergic drugs often improve motivation is likely because they increase desire, not pleasure.
Klavot
Posted by linkadge on January 20, 2007, at 7:51:47
In reply to Re: Zoloft and dopamine reuptake inhibition, posted by Klavot on January 20, 2007, at 2:53:48
Comparing wellbutrin to zoloft in terms of dopamine reuptake inhibition doens't make a whole lot of sense for reasons mentioned before.
With wellbutrin the dopamine reuptake inhibition will be relatively unnaposed by serotonin reuptake inhibition, wherase with zoloft you've got all the serotonin action opposing the dopamine action.
I certainly noticed switching from celexa to zoloft. I could certainly feel dopamine reuptake inhibtion. Thought some might question that sense.
Linkadge
Posted by blueberry1 on January 20, 2007, at 8:25:45
In reply to Zoloft and dopamine reuptake inhibition, posted by Quintal on January 19, 2007, at 21:12:03
I don't remember where I saw it, but there was a chart showing the affinity of wellbutrin versus zoloft for dopamine reuptake. Zoloft was significantly higher than wellbutrin. But it went on to explain that the chart is deceiving, because at therapeutic doses wellbutrin is actually higher. They said it takes 300mg zoloft for the dopamine part to kick in. They also said that it is not wellbutrin itself that has the dopamine action, but rather its metabolites that are 20 times stronger than the wellbutrin itself. And that depending on how a person's unique chemistry breaks down and metabolizes wellbutrin, the effects vary, resulting in either increased effectiveness or increased adverse effects with less effectiveness.
The one time I tried zoloft I swear I felt dopamine the very first day. It felt a lot like when I tried tyrosine supplements. And that was at just 25mg.
So who knows. I don't think any website or researcher really does. It either works or it doesn't, and it's just that simple.
I've tried dopamine strategies, such as tyrosine, low dose amisulpride, ritalin and adderall. They did not increase pleasure at all. But they did increase motivation to get things done. Motivation to do them, but no pleasure in doing them. So I wonder about dopamine's reputation as the pleasure chemical. I believe the whole thing is much more complicated, involving interplay between all the chemicals. You can't change one without causing a cascade effect that changes the others.
Anyway, zoloft and dopamine? It felt that way to me. Lexapro on the other hand felt like pure serotonin, very much like taking 5htp supplements.
Posted by naughtypuppy on January 20, 2007, at 9:34:16
In reply to Re: Zoloft and dopamine reuptake inhibition » halcyondaze, posted by Quintal on January 20, 2007, at 0:02:44
The Preskorn column makes a lot of sense. Essentially it says that you would have to take enough sertraline to OD an elephant in order to have any clinically significant dopamegenic activity. Comparing two meds mg. vs mg. only means that you have to take a bigger pill for the same activity.
Posted by Quintal on January 20, 2007, at 10:28:09
In reply to Zoloft and dopamine reuptake inhibition, posted by Quintal on January 19, 2007, at 21:12:03
Hmmm......when I took low dose amisulpride it felt very pleasurable to me at first - like the feeling of well-being and contentment I get from an opiate but without the warm haze and lethargy.
I've been wondering if the severe nausea vomiting I suffered from Zoloft more than other SSRIs was due to the additional DA reuptake properties?
Q
Posted by halcyondaze on January 20, 2007, at 10:55:54
In reply to kindof unhelpful if effexor is not included :( (nm), posted by iforgotmypassword on January 20, 2007, at 2:16:41
It was included.
Its effects on DA were negligible.
Posted by halcyondaze on January 20, 2007, at 10:57:41
In reply to Re: Zoloft and dopamine reuptake inhibition, posted by Quintal on January 20, 2007, at 10:28:09
For me, the only drugs that have helped my depression are Adderall, Parnate, and Zoloft.
This leads me to believe that I require DA reuptake inhibition for an AD to work and that there is some similar thread in these three meds.
Posted by Larry Hoover on January 20, 2007, at 13:50:46
In reply to kindof unhelpful if effexor is not included :( (nm), posted by iforgotmypassword on January 20, 2007, at 2:16:41
From the receptor affinity database:
http://kidb.cwru.edu/pdsp.phpDopamine Transporter Ki (nM) for various substrates mentioned in this thread (range):
Ritalin 21-50
Adderal no values for any amphetamines
Zoloft 22-315 (latter value is an outlier; all others similar to Ritalin)
Wellbutrin 520-950
Tranylcypromine 5100 (single value)
Effexor 3070-9300
Paxil 268-963It should also be noted that there are a number of pharmakokinetic parameters influencing the relative effect of these meds at this transporter, including dose, molecular weight, bioavailability, first pass metabolism, and CNS uptake, to say nothing of genetic influences. Also, as mentioned, active metabolites are not considered here (but many are listed in the above database, if you know what they are).
Lar
Posted by Quintal on January 20, 2007, at 14:19:43
In reply to Re: kindof unhelpful if effexor is not included :(, posted by Larry Hoover on January 20, 2007, at 13:50:46
Thank you for the link and info Larry.
So it seems Zoloft is in the same ballpark as Ritalin in terms of dopamine reuptake inhibition? The tranylcypromine is a surprise coming out the weakest, but being an MAOI it does't operate via reuptake inhibition in any case, so that result is not an accurate indicator of its effect on dopamine levels.
I wonder if Zoloft has been used in ADHD? Has anyone had ADHD symptoms improve while taking Zoloft?
Q
Posted by halcyondaze on January 20, 2007, at 14:42:24
In reply to Zoloft and dopamine reuptake inhibition, posted by Quintal on January 20, 2007, at 14:19:43
The chart I refer to from the Psychiatry book was exclusively on dopamine reuptake inhibition.
There's another chart with regard to blockade of DA receptors, in which the affinity is as follows:
Amoxapine: approx 5.5
Trimipramine: approx 0.5
Clomipramine: approx 0.5
Remeron: approx 0.2
Serzone: approx 0.2
And less than 0.1: Imiprimine, Amitriptyline, Nortriptyline, Desipramine, Doxepin, Protriptyline. Less than 0.01 is Prozac, Luvox, and Trazodone.It really depends on what mechanism you're looking at.
These charts have relative potencies at therapeutic dosing ranges but, without explanation as to the exact mechanism of each drug, are very difficult to compare.
> From the receptor affinity database:
> http://kidb.cwru.edu/pdsp.php
>
> Dopamine Transporter Ki (nM) for various substrates mentioned in this thread (range):
>
> Ritalin 21-50
> Adderal no values for any amphetamines
> Zoloft 22-315 (latter value is an outlier; all others similar to Ritalin)
> Wellbutrin 520-950
> Tranylcypromine 5100 (single value)
> Effexor 3070-9300
> Paxil 268-963
>
> It should also be noted that there are a number of pharmakokinetic parameters influencing the relative effect of these meds at this transporter, including dose, molecular weight, bioavailability, first pass metabolism, and CNS uptake, to say nothing of genetic influences. Also, as mentioned, active metabolites are not considered here (but many are listed in the above database, if you know what they are).
>
> Lar
Posted by Quintal on January 20, 2007, at 14:56:02
In reply to Re: Zoloft and dopamine reuptake inhibition, posted by halcyondaze on January 20, 2007, at 14:42:24
Amoxpaine is a derivative of the antipsychotic Loxapine, and one of its metabolites is a dopamine antagonist, so I guess that explains the result.
Q
Posted by linkadge on January 20, 2007, at 15:32:42
In reply to Re: Zoloft and dopamine reuptake inhibition, posted by Quintal on January 20, 2007, at 14:56:02
I have taken all the SSRI's and found that in terms of concentration, it was a tossup between zoloft and prozac.
Actually I felt pretty good when changing from prozac to zoloft (with some zoloft still in my system)
Possably a combination of mild dopamine reuptake inhibition with 5-ht2c blockade from prozac.
Linkadge
Posted by linkadge on January 20, 2007, at 15:35:07
In reply to Re: Zoloft and dopamine reuptake inhibition, posted by Quintal on January 20, 2007, at 14:56:02
What do you make of the possbility of SSRI's dammging the heart in a similar manner to other 5-ht2b agonists like fenfluramine?
Some of the dopamine agonists have also recently been linked to cardiac vulvopathy via secondary binding to cardiac 5-ht2b receptors.
We had a discussion a week or so ago and could have used your input.
Linkadge
Posted by halcyondaze on January 20, 2007, at 15:58:53
In reply to Re: Now that you're here larry, posted by linkadge on January 20, 2007, at 15:35:07
This is the book these charts are from:
<< http://i2.photobucket.com/albums/y32/tygereyes83/Book.jpg >>
1) RELATIVE AFFINITIES OF ANTIDEPRESSANTS FOR BLOCKING MUSCARINIC RECEPTORS
<< http://i2.photobucket.com/albums/y32/tygereyes83/Muscarinic.jpg >>
2) RELATIVE AFFINITIES OF ANTIDEPRESSANTS FOR BLOCKING HISTAMINIC RECEPTORS
<< http://i2.photobucket.com/albums/y32/tygereyes83/Histaminic.jpg >>
3) RELATIVE AFFINITIES OF ANTIDEPRESSANTS FOR BLOCKING THE REUPTAKE OF NOREPINEPHRINE
<< http://i2.photobucket.com/albums/y32/tygereyes83/NEreuptake.jpg >>
4) RELATIVE AFFINITIES OF ANTIDEPRESSANTS FOR BLOCKING ALPHA1ADRENORECEPTORS
<< http://i2.photobucket.com/albums/y32/tygereyes83/Alpha1adreno.jpg >>
5) RELATIVE AFFINITIES OF ANTIDEPRESSANTS FOR BLOCKING THE REUPTAKE OF SEROTONIN
<< http://i2.photobucket.com/albums/y32/tygereyes83/5HTreuptakeblock.jpg >>
6) RELATIVE AFFINITIES OF ANTIDEPRESSANTS FOR BLOCKING 5HT-2A RECEPTORS
<< http://i2.photobucket.com/albums/y32/tygereyes83/5HT2receptorblock.jpg >>
7) RELATIVE AFFINITIES OF ANTIDEPRESSANTS FOR BLOCKING THE REUPTAKE OF DOPAMINE
<< http://i2.photobucket.com/albums/y32/tygereyes83/DAreuptakeblock.jpg >>
8) RELATIVE AFFINITIES OF ANTIDEPRESSANTS FOR BLOCKING DOPAMINE RECEPTORS
<< http://i2.photobucket.com/albums/y32/tygereyes83/DAreceptorblock.jpg >>
Posted by Quintal on January 20, 2007, at 16:31:21
In reply to UPLOADED PICS OF ALL CHARTS FROM BOOK:, posted by halcyondaze on January 20, 2007, at 15:58:53
Thank you for uploading the photos hal. The book seems very thorough. I had a look on Amazon and it's very expensive "Psychiatry Therapeutics: second edition". Did you get it second hand? I would myself but Amazon UK only has new copies for sale. Can you recomend any other similar books?
I've been looking for a way to upload photos onto the web for viewing here. Do you have to pay for an account with www.photobucket.com?
Q
Posted by halcyondaze on January 20, 2007, at 16:48:56
In reply to Re: UPLOADED PICS OF ALL CHARTS FROM BOOK: » halcyondaze, posted by Quintal on January 20, 2007, at 16:31:21
> Thank you for uploading the photos hal. The book seems very thorough. I had a look on Amazon and it's very expensive "Psychiatry Therapeutics: second edition". Did you get it second hand? I would myself but Amazon UK only has new copies for sale. Can you recomend any other similar books?
>
> I've been looking for a way to upload photos onto the web for viewing here. Do you have to pay for an account with www.photobucket.com?
>
> Q
>Let's just say that I work in psychiatry and I can receive clinical texts at discounted prices. All of the clinical texts will be that expensive, unfortunately, unless you belong to the American Psychiatric Association or a similar organization - but I can recommend some of my other favorites if price isn't an issue.
Photobucket is inded free.
Posted by Phillipa on January 20, 2007, at 17:41:23
In reply to Re: UPLOADED PICS OF ALL CHARTS FROM BOOK: » halcyondaze, posted by Quintal on January 20, 2007, at 16:31:21
Q photobucket is free we've used it for pics. Love Phillipa
Posted by Larry Hoover on January 21, 2007, at 7:56:17
In reply to Re: Now that you're here larry, posted by linkadge on January 20, 2007, at 15:35:07
> What do you make of the possbility of SSRI's dammging the heart in a similar manner to other 5-ht2b agonists like fenfluramine?
I think we'd have seen the sentinel cases by now, the most sensitive among us. As I recall, the analogy to carcinoid syndrome was used to describe the likely mechanism behind the phen-fen phiasco (sic).
> Some of the dopamine agonists have also recently been linked to cardiac vulvopathy via secondary binding to cardiac 5-ht2b receptors.
Didn't know that. Might be worth a second thought.
> We had a discussion a week or so ago and could have used your input.
>
>
> LinkadgeYa got a link, link?
Lar
Posted by linkadge on January 21, 2007, at 8:53:54
In reply to Re: Now that you're here larry » linkadge, posted by Larry Hoover on January 21, 2007, at 7:56:17
We started by discussing how the cabergoline and other dopamine agonists can cause vulvopathy. We also discussed how mice lacking the serotonin transporter develop cardiac valve diseases.
http://www.dr-bob.org/babble/20070107/msgs/720797.html
Linkadge
Posted by blueberry1 on January 21, 2007, at 11:04:52
In reply to UPLOADED PICS OF ALL CHARTS FROM BOOK:, posted by halcyondaze on January 20, 2007, at 15:58:53
Interesting pics. Much appreciated. I couldn't help but notice a few things that seemed puzzling. Could anyone explain?
Why does wellbutrin not show any norepinephrine reuptake?
Why does effexor not show any norepinephrine reuptake? And very little serotonin reuptake? What does effexor do if it doesn't do these two things it is claimed to do?
Comment on paxil. In a survey of hundreds of physicians for their opinions, the results were that paxil was a top antidepressant in terms of efficacy. I wonder if that has anything to do with what these pics show. That is, it is not only the strongest serotonin reuptake inhibitor by a long shot, it also has a fair amount of dopamine and norepinephrine reuptake compared to others.
Zoloft's dopamine reuptake looks astounding. I wonder though what dose it takes to get that?
Posted by Phillipa on January 21, 2007, at 19:12:36
In reply to Re: UPLOADED PICS ....Questions on These, posted by blueberry1 on January 21, 2007, at 11:04:52
Blueberry the print was too small for me to read so are you saying paxil and zoloft are good meds both for anxiety and depression or the opposite? Thanks Phillipa
Posted by tensor on January 22, 2007, at 5:35:33
In reply to Zoloft and dopamine reuptake inhibition, posted by Quintal on January 19, 2007, at 21:12:03
I think the difference between Zoloft's and Wellbutrin's dopamine action is pretty good explained by SHELDON H. PRESKORN, MD.:
Tables 1 and 2 provide the data needed to understand why bupropion affects the dopamine and norepinephrine uptake pumps while sertraline does not. The differences between the plasma levels of sertraline and those of bupropion plus its metabolites occur because of rather than in spite of the substantial difference in the binding affinity of bupropion and sertraline for their respective targets. The levels of sertraline are so low because of its high binding affinity for the serotonin uptake pump. In contrast, the level of hydroxybupropion alone is 100 times higher than the level of sertraline because such high concentrations are needed to block the dopamine and norepinephrine uptake pumps, given the low affinity of bupropion for these targets.
Table 1. Mean (and standard deviation) trough plasma levels (ng/ml) of bupropion and its three major metabolites in patients on 450 mg/day of immediate release forumulation.*
Bupropion 33 (34)
Hydroxybupropion 1452 (666)
Erythrohydrobupropion 138 (86)
Threohydrobupropion 671 (425)Table 2. Relationship between sertraline dose, mean trough plasma level and magnitude of serotonin uptake inhibition in platelets.*
Dose 50 mg
Mean drug level 16 ng/ml
SE uptake inhibition of platelets 80%Based on the comparison of binding affinities shown in Figure 1, the levels of sertraline needed to block the dopamine uptake pump are clearly lower than the levels of bupropion needed to block this pump. However, the serotonin uptake pump would be saturated at such concentrations of sertraline. In an earlier column,19 the dose-(and hence concentration-) dependent nature of sertraline's inhibition of the serotonin uptake pump was presented. Based on those results, a dose of 200 mg/day in the average patient produces sertraline concentrations that yield over 95% inhibition of the serotonin uptake pump. Given the difference in sertraline's binding affinity for the serotonin versus the dopamine uptake pump, the dose of sertraline needed to block the dopamine uptake pump would be substantially higher than 200 mg/day. Nevertheless, this statement is tentative since there have been no formal, human studies done to determine what dose of sertraline would be needed to achieve concentrations of sertraline sufficient to block dopamine uptake nor how many people could tolerate such a dose in terms of the serotonin adverse effects likely to result from such a saturation of the serotonin uptake pump.
The bottom line is that the 20-fold difference between sertraline and bupropion in binding affinity for the dopamine uptake pump (Figure 1) is more than offset by the 100-fold difference in the drug concentrations of each achieved under their usual dosing conditions (Tables 1 and 2). Parenthetically, notice that the difference in concentration between these two drugs is several times higher than the difference in their dose (50 to 450 mg/day, respectively). Remember that dose is only one of the two factors that determine drug concentration (Equation 2). That is the reason why dose is an imperfect way of assessing the potency of a drug in terms of an action.
-------The whole article can be read at http://www.preskorn.com/columns/0001.html
/Mattias
Posted by sukarno on January 22, 2007, at 8:46:22
In reply to Re: Zoloft and dopamine reuptake inhibition, posted by linkadge on January 20, 2007, at 15:32:42
With all of the sexual dysfunction that sertraline (Zoloft) causes, I would find it difficult to believe if it had any significant dopamine reuptake blocking properties.
If anything, when you flood the brain with serotonin as is the case with SSRIs via serotonin reuptake inhibition, it tends to antagonise dopamine.
Amoxapine is a dopamine antagonist as far as I know (someone posted here about amoxapine) so it couldn't be a DA reuptake inhibitor.
Tianeptine (Stablon) would be a better bet if you couldn't find remaining supplies of amineptine (Survector). One researcher theorised that tianeptine's antidepressant effect might be more related to a dopaminergic mechanism vis a vis the D2/D3 receptors. Of course it also has been proven to help restore hippocampal volume.
I wouldn't take tianeptine with sertraline (or any other SSRI), since tianeptine accelerates the reuptake of serotonin while sertraline is doing the exact opposite. It just wouldn't make sense to use both, unless the true antidepressant effect of tianeptine lies in its alleged mild dopaminergic action.
Just my $0.02
Go forward in thread:
Psycho-Babble Medication | Extras | FAQ
Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.org
Script revised: February 4, 2008
URL: http://www.dr-bob.org/cgi-bin/pb/mget.pl
Copyright 2006-17 Robert Hsiung.
Owned and operated by Dr. Bob LLC and not the University of Chicago.