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Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 1 to 14 of 14. This is the beginning of the thread.
Posted by Shawn. T. on April 13, 2003, at 18:59:16
I am writing an article about the most promising future drug treatment options for psychiatric disorders. I would like to know if any of you have suggestions that are not already on my rough initial list. I'm interested in drugs that have not yet been marketed. However, theoretical drugs that have not yet been synthesized would not make the list; for example, a 5-HT-moduline blocker wouldn't make it. JR Becker has helped me a bit with this list; I'd like to get more opinions to insure a well rounded list.
1. CRF1 antagonists (for depression/anxiety)
2. AVP V1B receptor antagonists (for anxious-retarded depression). SSR149415 is an example.
3. NK1 antagonists aka substance P blockers (for anxiety disorders)
4. Benzodiazepine partial agonists (for anxiety disorders and possibly others). Imidazenil and RWJ-51204 are examples.
5. Cholecystokinin CCKB antagonists (for panic/anxiety disorders)
6. 5-HT1A agonists (these may not make the final cut)
7. Melanin-concentrating hormone MCH1 antagonists (perhaps for depression w/hyperphagia). SNAP-7941 is an example.
8. One of the 5-HT2C antagonists, perhaps a drug from Servier called agomelatine that is both a 5-HT2C antagonist and melatonin receptor agonist. It seems to be especially useful for people with sleep disturbances.
9. PKC alpha blockers (for bipolar disorder). Tamoxifen is an example, but I'd prefer to see something available with fewer side effects.
10. AMPA receptor modulators like the Ampakines from Cortex Pharmaceuticals (perhaps for schizoaffective disorders, mild cognitive impairment, and possibly others)Note that I've removed NMDA antagonists, 5-HT1B ligands, MIF1 analogues, and unreleased dual reuptake inhibitors from the list. I may choose to add the alpha-2-adrenoceptor partial agonist moxonidine (for ADHD) pending my evaluation of how Eli Lilly perceives the drug's potential. I still question the usefulness of glucocorticoid antagonists given the advantages of CRF antagonists, but they'll certainly be useful for Cushing's Syndrome. Note that the article will be posted on my website ( http://www.neurotransmitter.net ).
Thanks for any suggestions,
Shawn
Posted by jaby on April 14, 2003, at 11:52:41
In reply to Please help with my list of promising future drugs, posted by Shawn. T. on April 13, 2003, at 18:59:16
Shawn,
Why the removal of NMDA antagonists? Because there are some already or because their not very efficacious? Also, what do you see as lamictal's primary mechanism of action (particularly the activating component of it). Do you know anything about rilutek/riluzole?
Thanks.
Posted by Ritch on April 14, 2003, at 13:09:54
In reply to Please help with my list of promising future drugs, posted by Shawn. T. on April 13, 2003, at 18:59:16
> I am writing an article about the most promising future drug treatment options for psychiatric disorders. I would like to know if any of you have suggestions that are not already on my rough initial list. I'm interested in drugs that have not yet been marketed. However, theoretical drugs that have not yet been synthesized would not make the list; for example, a 5-HT-moduline blocker wouldn't make it. JR Becker has helped me a bit with this list; I'd like to get more opinions to insure a well rounded list.
>
> 1. CRF1 antagonists (for depression/anxiety)
> 2. AVP V1B receptor antagonists (for anxious-retarded depression). SSR149415 is an example.
> 3. NK1 antagonists aka substance P blockers (for anxiety disorders)
> 4. Benzodiazepine partial agonists (for anxiety disorders and possibly others). Imidazenil and RWJ-51204 are examples.
> 5. Cholecystokinin CCKB antagonists (for panic/anxiety disorders)
> 6. 5-HT1A agonists (these may not make the final cut)
> 7. Melanin-concentrating hormone MCH1 antagonists (perhaps for depression w/hyperphagia). SNAP-7941 is an example.
> 8. One of the 5-HT2C antagonists, perhaps a drug from Servier called agomelatine that is both a 5-HT2C antagonist and melatonin receptor agonist. It seems to be especially useful for people with sleep disturbances.
> 9. PKC alpha blockers (for bipolar disorder). Tamoxifen is an example, but I'd prefer to see something available with fewer side effects.
> 10. AMPA receptor modulators like the Ampakines from Cortex Pharmaceuticals (perhaps for schizoaffective disorders, mild cognitive impairment, and possibly others)
>
> Note that I've removed NMDA antagonists, 5-HT1B ligands, MIF1 analogues, and unreleased dual reuptake inhibitors from the list. I may choose to add the alpha-2-adrenoceptor partial agonist moxonidine (for ADHD) pending my evaluation of how Eli Lilly perceives the drug's potential. I still question the usefulness of glucocorticoid antagonists given the advantages of CRF antagonists, but they'll certainly be useful for Cushing's Syndrome. Note that the article will be posted on my website ( http://www.neurotransmitter.net ).
>
> Thanks for any suggestions,
>
> Shawn
I think it would be interesting to see a cost-competitive 5HT-3 antagonist, or even a 5HT3-antagonist+SRI med. (for anxiety disorders-as an alternative for people who are especially sensitive to SSRI GI side effects such as nausea, diarrhea, and acid reflux).
Posted by Shawn. T. on April 15, 2003, at 20:27:15
In reply to Re: Please help with my list of promising future drugs, posted by jaby on April 14, 2003, at 11:52:41
Regarding the NMDA antagonists, I don't believe that the likelihood of FDA approval of these drugs for psychiatric disorders is especially high. I'm also looking for drugs that get right to the source of the problem.
The question on Lamictal is challenging... here is my description of Lamictal's (lamotrigine) mechanism of action:
Lamotrigine blocks use- dependent voltage- sensitive sodium channels. The drug preferentially binds to the channel pore in inactivated but not resting sodium channels; its inhibition of sodium channels is therefore increased by neuronal depolarization. Lamotrigine also inhibits N-type and P/Q-type voltage- activated calcium channels.
-I find it difficult to argue that its mechanism of action that leads to efficacy in say bipolar disorder is solely sodium channel blockade. I'm not sure what role its actions at voltage- gated calcium channels play, but I'll speculate and say that they're probably less important. Likewise, both types of effect are probably important for its efficacy as an anticonvulsant.
With regards to the activating component of Lamictal, a reduction in glutamate release by the drug is likely responsible. (See http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10496235&dopt=Abstract ). The drug reduces glutamate release via its actions on sodium channels and perhaps N-type calcium channels (I'm not sure about P/Q-type channels). An alternative explanation for Lamictal's activating effect is that it negatively modulates the effects of GABA (see http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11955522&dopt=Abstract ); I can't offer any proof for this idea, so it's pure speculation.
Riluzole seems to be a neuroprotective drug used to treat amyotrophic lateral sclerosis/ motor neuron disease. I believe that it acts similarly to Lamictal (See http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12645037&dopt=Abstract ). I believe that riluzole may be more potent at sodium channels than Lamictal. If you need any references on any of this, I'd be glad to give them to you.
Shawn
Posted by Shawn. T. on April 15, 2003, at 20:34:20
In reply to Re: Please help with my list of promising future drugs » Shawn. T., posted by Ritch on April 14, 2003, at 13:09:54
I might add a section about other drugs that didn't make the list for one reason or another. An inexpensive 5-HT3 antagonist would probably make that list; I'm sure that it would also be welcomed by people with some types of irritable bowel disease. I like the idea of combining a 5-HT3 antagonist with another function, but I think that the last thing we need is another SSRI. Part of the function of my article will be to make people aware that evidence based medicine will soon shoo away drugs like SSRI's.
Shawn
Posted by BrittPark on April 16, 2003, at 14:38:52
In reply to Please help with my list of promising future drugs, posted by Shawn. T. on April 13, 2003, at 18:59:16
One class of drug that is missing from your list is opioidergics. I suppose that should not be surprising since no one is trying to develop an opioid as treatment for depression. Opioids have been shown clinically (search medline for tramadol, and buprenorphine and you'll find a couple of studies) and anecdotally to be effective for treating depression. There are several citizens of PB who are being successfully treated with opioids. I'm one of them.
The major problem with opioids for depression, medically not legally, is tolerance. Some people develop tolerance to opioids rapidly and others don't. I take 1 5/500 vicodin daily and it helps with my depression/anxiety. If I were able to take it at a considerably larger dose, and not develop tolerance, I think that it would largely return me to normal functioning.
My point, and I do have one, is that a company called Pain Therapeutics is developing formulations of Morphine and Oxycodone with tiny admixtures of naltrexone (an opioid receptor antagonist). The interesting thing about these formulations is that they have been demonstrated in animals not to induce tolerance. Assuming that the euphoric characteristics (I'm assuming that is why opioids work as ADs) tag along with their analgesic characteristics, these could be breakthrough drugs for TRD. I've written to Pain Therapeutics suggesting that they investigate this possibility. I've received no response.
What might be interesting journalistically is a look into the almost complete absence of research into the opioidergic systems' involvement with affective disorders. I think you'll find that this state of affairs holds not for scientific reasons, but for political.
Thanks for the opportunity to spout off about my pet peeve ;)
Britt Park, PhD (Structural Biology)
Posted by bretbe on April 17, 2003, at 0:26:19
In reply to Please help with my list of promising future drugs, posted by Shawn. T. on April 13, 2003, at 18:59:16
Question:
I'm not real savvy here on all the technical psychopharmocological aspects here, but I'm very interested in what you've found on GABA and what you said about Lamictal. I had a very bad reaction to Lamictal, similar to what I had with Welbutrin, Lithium, and Buspar, in that my anxiety went out the roof...intense, wound up pressure that I thought head would explode...SUBJECTIVE FEELING, not actual physical symptoms such as hypertensive crises...mental pain all the way. Anyway, the only med that has had any significant positive effect is Klonopin and, as I understand it, Benzo's work on the GABBA system...perhaps. Anyway, my question is about your statement about Lamictal was your comment about negatively impacting GABBA. It appears that highly activating meds make my symptoms worse (intense mental anxiety, dysphoria & non-depressed depression, i.e., normal energy but doom and gloom in head), while benzo's take some of the sting out. Also, valproic acid (Depakote) initially felt nice at low doses and supposedly works as GABBA agonist. Sooo, could it be that my particular variant of depression/anxiety is primarly related to GABBA? I mean, does it make any kind of sense, based on your info, that low GABBA is my problem while augmenting GABBA is my cure?Any thoughts based on your research?
Posted by Shawn. T. on April 17, 2003, at 23:13:36
In reply to Re: Please help with my list of promising future drugs, posted by BrittPark on April 16, 2003, at 14:38:52
I suppose that I'm somewhat biased against using opioids to treat depression. However, considering the currently available treatments for depression, I can agree that opioids should remain viable options for treatment resistant patients. I question how competitive opioids will be once a wider and more effective range of antidepressants are released. I think it's difficult to judge how the efficacy/side effect profile of an opioid agonist/antagonist combination might compare to something like a CRF antagonist. Based on my own knowledge and bias, I don't see opioids as having much of a place in the future of antidepressant treatments; they simply don't attack the root of the problem directly enough for me to believe in their potential. I'll still probably make a note about opioids and other drugs like NMDA antagonists at the end of my article; thanks for the suggestion.
Shawn
Posted by Shawn. T. on April 18, 2003, at 0:04:59
In reply to Re: Please help with my list of promising future drugs, posted by bretbe on April 17, 2003, at 0:26:19
I looked more deeply into the relationship between Lamictal and GABA. One report has found that Lamictal increases cerebral GABA levels by 25% after four weeks (see http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11839834&dopt=Abstract ). Another has found no change in plasma GABA levels with Lamictal (see http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12691776&dopt=Abstract ). However, two other reports have found that Lamictal decreases GABA- mediated synaptic transmission (see http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11955522&dopt=Abstract ).
I think it's difficult to judge exactly how Lamictal affects GABA- mediated effects in the brain after chronic treatment. I hesitate to suggest that Lamictal is an anti-GABAergic drug; that just doesn't fit well with the profile of an anticonvulsant. The relationship between Lamictal and GABA is definitely complex, so making a sure judgment is difficult. On the other hand, Lamictal's actions on glutamate release are well understood and accepted. Drugs that block the effects of glutamate at NMDA and perhaps other types of glutamate receptors are known to cause hyperactivity. I think the connections among Lamictal, decreased glutamate release, and activation are rather clear; conclusions involving GABA are not.
There is a possible link between GABA and depression in some subtypes of depression (see http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11253954&dopt=Abstract). I did find one report of a connection between recurrent unipolar depression and a variation of the GABA-A receptor alpha 5 subunit gene. I'm really not that familiar with the relationship between depression and GABA, so I can't really give you a good overview of the topic. I can say that your intuition is probably correct.
Valproic acid likely increases GABAergic transmission by reducing the expression of GAT-1 and GAT-3 GABA transporter proteins; it's currently unknown how the drug causes this effect. That means that valproic acid might reduce the reuptake of GABA into neuron terminals, but no one knows if this occurs in humans at normal doses. I'm personally really interested in how valproic acid works in bipolar disorder; I doubt that its GABAergic effects play much of a role.
Shawn
Posted by bretbe on April 18, 2003, at 0:50:33
In reply to Re: Please help with my list of promising future drugs » bretbe, posted by Shawn. T. on April 18, 2003, at 0:04:59
Thanks Shawn,
BTW, what is your background and how does one get into your field (or is this just a hobby)?
Thanks again!
Bret
Posted by BrittPark on April 18, 2003, at 1:37:49
In reply to Re: Please help with my list of promising future drugs » BrittPark, posted by Shawn. T. on April 17, 2003, at 23:13:36
Could I ask why you are biased against opioids? Tolerance is one reason to be leary, I suppose, but given an opioid formulation that didn't induce tolerance, would you still be biased? Without the tolerance opioids seem to be far better ADs than any of the ADs we have. The action is immediate, so one can tell whether the drug helps very quickly as opposed to the 6 to 8 weeks needed for traditional ADs, and if an opioid works, it works more completely than any of the ADs we have. The question I ask myself is why then has so little research effort been made to discover ways to block the habituation reaction to opioids. I except Pain Therapeutic's research, which is singular.
I've always been a bit puzzled by the psychiatric attitude towards opioids. Doctors are quite willing to prescribe stimulants, schedule II drugs like many opioids, to treat ADHD or as an augmentation strategy for the treatment of depression, but give patients a suspicious glare if the subject of opioids is broached. I know of no clinical evidence that amphetamines are in fact less habituating and addictive than opioids. In fact my psychiatrist considers cocaine (similar in effect to amphetamines) addiction the most pernicious of all addictions.
As a parting note take a look at this 1996 editorial from Biological Psychiatry. http://www.sciencething.org/Callaway.pdf
Posted by Shawn. T. on April 18, 2003, at 15:38:19
In reply to Re: Please help with my list of promising future drugs » Shawn. T., posted by BrittPark on April 18, 2003, at 1:37:49
I should make it clear that I'm somewhat biased against opioids as a treatment option for large numbers of people near the latter years of this decade. With regards to the current situation, I agree that they are reasonable treatment options. I would like to see more information on the combination of drugs that you speak of; without knowing more, I don't feel that I can make a reliable judgment of their usefulness in the competitive market of the future. The side effects of opioids are clearly part of my bias. I'm aware that an opioid that doesn't induce tolerance may be devoid of certain side effects like potential neurotoxic effects, but I'd really like to see reports of in vivo neurological and cognitive studies on the combination of opioids. Basically my view on this topic is that I can't compare/contrast the opioid agonist/antagonist combination to the other drugs on my list. I'm not arguing that no one should take opioids to treat depression; I just feel like I cannot make a well informed decision to include them.
Shawn
Posted by Shawn. T. on April 18, 2003, at 16:02:08
In reply to Thanks Shawn!, posted by bretbe on April 18, 2003, at 0:50:33
I would say that I'm engaging in a hobby at the current time, but I plan to make it my profession in the future. Most of my educational background is in computer science. I'm still an undergraduate; I recently made the switch to a major in biology. I've been interested in how drugs work for several years, but I've only taken a strong interest in neuroscience research since roughly a year ago. I'm a quick learner, so I've covered a lot of ground.
If you want to learn about neuroscience as a hobby, the best way to start off is to read a few books on neuroscience; they don't have to be text books, just broad overviews to introduce you to some of the jargon and concepts. A general knowledge of biology would also be helpful. The next step would probably be to just delve into a certain topic; you could begin by researching it on the web and then move on to searching through PubMed. You'll want to read the PubMed tutorial to insure that you understand how to create tight search strings. A medical dictionary like the one at http://cancerweb.ncl.ac.uk/cgi-bin/omd?action=Home&query= might be helpful. Once you tire of one topic, move along to another (perhaps a related topic). I began with researching the pharmacology of serotonergic drugs, then moved to researching serotonin, then to mood disorders, and finally moved on to several other topics. I initially took lots of notes, but then I realized that creating HTML pages with dozens of logically organized abstracts on them could allow me to easily get the big picture on a certain topic. For a beginner, notes and bookmarks would probably be your best bets. In the end, perhaps the most important things you'll need are a good memory and a strong interest.
Shawn
Posted by Caleb462 on April 19, 2003, at 1:28:58
In reply to Re: Please help with my list of promising future drugs » BrittPark, posted by Shawn. T. on April 18, 2003, at 15:38:19
>I'm aware that an opioid that doesn't induce tolerance may be devoid of certain side effects like potential neurotoxic effects
Neurotoxic effects??
I don't know of any opiates or opiods that are neurotoxic. In fact, of all the abused drugs, opiods are generally the safest in physical terms.
This is the end of the thread.
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