GABA and Schizophrenia: The power of "unscientific" induction
I just Googled "GABA schizophrenia" after a bunch of inductive, intuitive thinking I've been doing on the subject over the past few weeks suddenly came to a culmination (light bulb moment). I arrived at this hypothesis in an "unscientific" way, and I "proved" it in my mind in a "unscientific" way. The light bulb was bright enough to constitute a "really quite likely importantly important proof of high probability." It pisses me off how Science claims it "unscientific" to use these types of theories before practice. Oh my god, it might overtly "bias" the scientific method (which is almost always covertly biased anyways). And, wow, "data" can come in forms that extend beyond numeric data! It may not be considered "scientific" data, but it is still "data" nonetheless. This is what I learned and loved about Economics---theory, theory, theory...then data, then practice. In Economics, starting with data instead of theory is called "Data Mining...Boooo!", whereas in Science this is called "Data Mining....Yaaaay!"
Not that I've read expert-extensively on the subject of Schizophrenia, but I have read a decent amount on the neurochemistry as well as the neurodevelopmental anatomy of Schizophrenia...and as far as I can remember, GABA-A was only mentioned in the sense that there were fewer of these receptors in Schizophrenics, neuroanatomically. There's absolutely nothing standard-textbook about the relationship between GABA and Schizophrenia.
My hypothesis pairs with the textbook Glutamate hypothesis (too much Glutamate), given the fact that on one hand Glutamate is a precursor to GABA via glutamic acid (catalyzed by GAD) (good!) and on the other hand the fact that Glutamate acts in an excitatory fashion at the NMDA receptors (bad!). Due the paradoxical nature of Glutamate in Schizophrenia, its primary causal role is moot, but its secondary role as a precursor to GABA points to the crucial axis of causality. I think the over-hyped Dopamine hypothesis is causally-secondary to the GABA hypothesis because *regulation* of excitability (GABA) begets *modulation* of excitability (Dopamine). (Yeah, they both regulate to a degree, but GABAergic pathways tend towards regulation whereas dopaminergic pathways tend towards modulation. And, oh my god, Western medicine might want to consider treating precursive/ontological/tentative causes rather than immediate/proximate causes). I think, however "unscientifically" I think, that GABA-related treatments would create a baseline for psychotherapeutic intervention that Dopamine-related treatments can never hope to reach. Dopamine antagonists (the de-facto treatment for Schizophrenia) basically dumb down schizophrenics to the point that, if sufficient quantities are given, they drool and lose the mental (and physical) capacity to function, at which point psychotherapy becomes useless. Learning = Dopamine. Attention = Dopamine. Executive control and the prefrontal cortex (assumed to be "dysfunctional" in Schizophrenia) = Dopamine. Oh my god, a drug may not be able to target every symptom of an illness, but it sure might be able to establish a more solid baseline for treatment, in which case we might have to employ measures that require these things called humans. Schizophrenics are not simply "crazy", and they're not these beasts that need to be numbed down to the point of drooling--they're simply very, very hard to understand, and dysfunctionally vulnerable in the context of our current society. What they need, first and foremost, is something to protect them from society, not vice-versa. Long live Foucault.
And sure enough:
"
Medscape: What do you consider the most important discoveries you and your colleagues have made during the past several years?
Dr. Benes: I think the first important discovery is that the GABA system is abnormal in schizophrenia and bipolar disorder. The next most important discovery, one that we're actively working on right now, is how molecular mechanisms result in GABA cell dysfunction and how these mechanisms differ in schizophrenia and bipolar disorder.
" (http://www.narsad.org/news/press/rg_2006/res2006-06-22.html)
AND:
July 26, 2007
New GABA-targeted Schizophrenia Medication in Phase II Clinical Trials - BioLineRX
Read more... Schizophrenia Medications in Development
BioLineRx Initiates Phase II Trial of a GABA-Enhanced Antipsychotic Medication Designed for the Treatment of Schizophrenia; Results of Phase IIa Trials Expected Q4 2007.
Marketing/Press release from BiolineRX:
BioLineRx Ltd. an Israeli drug development company, today announced the initiation of a Phase II clinical trial on schizophrenic patients for the maximal tolerated dose determination of BL-1020. BL-1020 is a first in class, orally available, GABA-enhanced antipsychotic for the treatment of schizophrenia.
"The dose ranges in this Phase II trials are based on results in previous clinical studies, which were performed on healthy volunteers. Based on our previous results, we believe that BL-1020 has the potential to be clinically efficacious with minimal therapy-limiting side effects. We very much look forward for the results of these Phase IIa trials expected sometime during the fourth quarter of 2007." commented Morris C. Laster, MD, chief executive officer of BioLineRx.
"There is a clear need for new antipsychotic drugs with increased efficacy and better tolerability, as currently available drugs while effective have patient compliance issues related to the drugs' side effect profile," said Professor Michael Davidson, Director Department of Psychiatry, Sheba MedicalCenter and the principal medical advisor of the trial. "Phase I studies have shown a very favorable safety profile for BL-1020, while retaining efficacy. We are looking forward to testing this novel compound on patients with schizophrenia."
About BL-1020
BL-1020 is an orally available GABA enhanced antipsychotic clinical candidate for the treatment of schizophrenia. Data from preclinical and phase I studies demonstrated that the compound may retain the efficacy of currently available typical and atypical antipsychotic drugs while achieving a much higher safety profile as evidenced by a lack of metabolic or extrapyramidal side effects.
Not that I've read expert-extensively on the subject of Schizophrenia, but I have read a decent amount on the neurochemistry as well as the neurodevelopmental anatomy of Schizophrenia...and as far as I can remember, GABA-A was only mentioned in the sense that there were fewer of these receptors in Schizophrenics, neuroanatomically. There's absolutely nothing standard-textbook about the relationship between GABA and Schizophrenia.
My hypothesis pairs with the textbook Glutamate hypothesis (too much Glutamate), given the fact that on one hand Glutamate is a precursor to GABA via glutamic acid (catalyzed by GAD) (good!) and on the other hand the fact that Glutamate acts in an excitatory fashion at the NMDA receptors (bad!). Due the paradoxical nature of Glutamate in Schizophrenia, its primary causal role is moot, but its secondary role as a precursor to GABA points to the crucial axis of causality. I think the over-hyped Dopamine hypothesis is causally-secondary to the GABA hypothesis because *regulation* of excitability (GABA) begets *modulation* of excitability (Dopamine). (Yeah, they both regulate to a degree, but GABAergic pathways tend towards regulation whereas dopaminergic pathways tend towards modulation. And, oh my god, Western medicine might want to consider treating precursive/ontological/tentative causes rather than immediate/proximate causes). I think, however "unscientifically" I think, that GABA-related treatments would create a baseline for psychotherapeutic intervention that Dopamine-related treatments can never hope to reach. Dopamine antagonists (the de-facto treatment for Schizophrenia) basically dumb down schizophrenics to the point that, if sufficient quantities are given, they drool and lose the mental (and physical) capacity to function, at which point psychotherapy becomes useless. Learning = Dopamine. Attention = Dopamine. Executive control and the prefrontal cortex (assumed to be "dysfunctional" in Schizophrenia) = Dopamine. Oh my god, a drug may not be able to target every symptom of an illness, but it sure might be able to establish a more solid baseline for treatment, in which case we might have to employ measures that require these things called humans. Schizophrenics are not simply "crazy", and they're not these beasts that need to be numbed down to the point of drooling--they're simply very, very hard to understand, and dysfunctionally vulnerable in the context of our current society. What they need, first and foremost, is something to protect them from society, not vice-versa. Long live Foucault.
And sure enough:
"
Medscape: What do you consider the most important discoveries you and your colleagues have made during the past several years?
Dr. Benes: I think the first important discovery is that the GABA system is abnormal in schizophrenia and bipolar disorder. The next most important discovery, one that we're actively working on right now, is how molecular mechanisms result in GABA cell dysfunction and how these mechanisms differ in schizophrenia and bipolar disorder.
" (http://www.narsad.org/news/press/rg_2006/res2006-06-22.html)
AND:
July 26, 2007
New GABA-targeted Schizophrenia Medication in Phase II Clinical Trials - BioLineRX
Read more... Schizophrenia Medications in Development
BioLineRx Initiates Phase II Trial of a GABA-Enhanced Antipsychotic Medication Designed for the Treatment of Schizophrenia; Results of Phase IIa Trials Expected Q4 2007.
Marketing/Press release from BiolineRX:
BioLineRx Ltd. an Israeli drug development company, today announced the initiation of a Phase II clinical trial on schizophrenic patients for the maximal tolerated dose determination of BL-1020. BL-1020 is a first in class, orally available, GABA-enhanced antipsychotic for the treatment of schizophrenia.
"The dose ranges in this Phase II trials are based on results in previous clinical studies, which were performed on healthy volunteers. Based on our previous results, we believe that BL-1020 has the potential to be clinically efficacious with minimal therapy-limiting side effects. We very much look forward for the results of these Phase IIa trials expected sometime during the fourth quarter of 2007." commented Morris C. Laster, MD, chief executive officer of BioLineRx.
"There is a clear need for new antipsychotic drugs with increased efficacy and better tolerability, as currently available drugs while effective have patient compliance issues related to the drugs' side effect profile," said Professor Michael Davidson, Director Department of Psychiatry, Sheba MedicalCenter and the principal medical advisor of the trial. "Phase I studies have shown a very favorable safety profile for BL-1020, while retaining efficacy. We are looking forward to testing this novel compound on patients with schizophrenia."
About BL-1020
BL-1020 is an orally available GABA enhanced antipsychotic clinical candidate for the treatment of schizophrenia. Data from preclinical and phase I studies demonstrated that the compound may retain the efficacy of currently available typical and atypical antipsychotic drugs while achieving a much higher safety profile as evidenced by a lack of metabolic or extrapyramidal side effects.