This might be my last post on Psycho-Babble

In this version, I added lots and lots of important information. I tried to do a better job of proofreading. This composition has become more of an essay through narrative.

There are 5076 words to get through. I imagine it will take you significantly more time for you to read than it was for me to write. Please indulge me and read the whole thing. You might find it worth saving to your computer.

In my *not-so-humble* opinion, I think that the majority of the people who continue to post on Psycho-Babble have evolved over time to have the ABSOLUTE WORST treatment behaviors. These people have been sabotaging their treatment for years and years, and probably those of others as well. If they continue down the paths that they have chosen for themselves, they will likely die depressed and without respite.

Obviously, I am not looking to be anyones friend today. I already have plenty of them. I just want to see at least a few suffering Psycho-Babble members move on to a higher plane of human consciousness the remission of depression.

My writing voice must have seemed overly enthusiastic, pedantic, pontificating, and egomaniacal. I used too many exclamation marks. I was perhaps too optimistic for some people, which is perfectly understandable. Hope is sometimes a curse.

I hope that it is only my tone / writing voice that people reject or are otherwise offended by. Nevertheless, I know that the content of my words is invaluable, and likely not to be seen again by any of you. I didnt get well by changing my treatment every few days. I never used Effexor as a PRN. I reject the type of self-medication that evolved on Psycho-Babble over the years. In my estimation, it has wasted years of peoples lives.

Remission is not found in knowing how histones are affected by lithium so as to effect neuroprotection in affective disorders and (other) neurodegenerative diseases.

Remission is not found by studying the modulatory effect of lithium on second-messenger cascades facilitated by the activity of transmembrane G-proteins, which in turn control the rate of adenyl-cyclase phosphorylation to form cyclic AMP (cAMP) from ATP.

Knowing the neurophysiology of low-dosage lithium administration has nothing to do with my decision to try it. Lithium worked for me, despite my ignorance of lithium pharmacology. I just opened my mouth and swallowed lithium pills.

I swallowed my first psychotropic pill in the Spring of 1982. It was a course of imipramine monotherapy that reached a dosage of 450 mg/day. Over the top? No. Aggressive Yes.

I got lucky in finding remission, but *only* while following the clinical guidelines and insights of notable doctors with good track records for treating TRD depression and other stubborn psychiatric disorders. Over the course of decades, I picked the brains of some of the best. Up until I found remission, I followed a treatment course / philosophy that took into consideration the clinical wisdom that I was exposed to over the course of 4 decades. I did NOT follow amateur armchair neuroscientists with nothing to offer *clinically* - how to get well.

1. In a way that relates to the observation and treatment of actual patients rather than theoretical or laboratory studies.

2. Of, relating to, or conducted in or as if in a clinic such as: involving direct observation of the patient. clinical diagnosis: based on or characterized by observable and diagnosable symptoms.

My advice to you is to study pure neuroscience less and clinical psychiatry more. Find out how to actually get well from the pioneers in psychiatry. Im just the messenger. Clinicians spend their time testing treatments on real people. They are much more concerned with discovering which treatments work rather than knowing how they work. In 2022, does anyone really know?

Who here knows what the accepted next step was to a failed course of Parnate monotherapy as practiced by the research team at Columbia Presbyterian in 1982? Does this clinical protocol have any value today, or is it just too old even though it still works?

I saw a Psycho-Babble member exclaim that there are no new drugs. First of all, thats not true. Even if it were, of what consequence is that to me, who attained remission using drugs that were available in 1996? In fact, one became available in 1970, and the other two were available in 1964. Too old? Not for me. Lucky for me that I remained unconcerned with the FDA approval dates of psychotropic medications.

1.Baron Shopsin
2.Frederick Quitkin
3.Robert Post
4.Patrick McGrath
5.Andrew Nierenberg
6.William Z. Potter

* Dr. Baron Shopsin was the protégé of Nathan Klein the father of psychopharmacology - while they were both performing their ground-breaking research at NYU in the 1960s. Shopsin wrote quite a few papers about lithium before it was approved. It was Ronald Fieve of Columbia Presbyterian who brought lithium to America and get it approved by the FDA. I dont think that the FDA was so quick to do this at first. In 1966, Dr. Fieve established the first lithium clinic in North America. In addition to lithium research, Shopsin, helped to describe a new diagnosis schizoaffective disorder. He proudly showed me his published book about this illness. I doubt that I would have understood it, though. He was a smart guy.

Baron Shopsin was way ahead of the curve in the study of investigational serotonergic drugs coming from France. None of the pro-serotonergic agents that he used on me were ever submitted to the FDA for approval. Trazodone was actually the first serotonin reuptake inhibitor that had no effect on the reuptake of norepinephrine (NE; noradrenaline). I was treated with it in 1982, a year after it was approved. This was while I was at Columbia Presbyterian as a subject in their clinical research program. At dosages used to treat depression, I found trazodone to be a very dirty drug. It has been reported to both agonize (stimulate) and antagonize (block) various serotonin receptors along with its serotonin reuptake properties. Trazodone acts at both postsynaptic and presynaptic 5-HT receptors. Its effects as a ligand at receptor binding sites are varied.

What I don't like about trazodone is that it is metabolized in the body into mCPP. Trazodone also blocks muscarinic acetylcholine receptors, making it anticholinergic. Acetylcholine receptors are ubiquitous in the hippocampus (memory center). THEORETICALLY, it can be argued that the anticholinergic properties of trazodone would actually enhance its therapeutic potential to treat depression. Sadly, trazodone is a poor antidepressant as demonstrated *clinically*. It has some use in insomnia and anxiety, but thats about it.

I miss Baron Shopsin, although our relationship ended up being strained later on. He had a mind that was particularly well-suited to operate in a frontier that had very little scientific guidance to develop treatment principles. I ate it up. I was one of the first people in the US to take a selective serotonin reuptake inhibitor. I was probably the only one to take a pure serotonin releaser (much like fenfluramine). These drugs were available to me 3-4 years before fluoxetine (Prozac) was approved. I took 3 serotonergic investigational compounds in sequence that I doubt more than a handful of psychiatrists had access to. The 3 pro-serotonergic drugs I tried were (in order):

1. Mixed 5-HT reuptake inhibitor and releaser Indalpine.
2. Selective 5-HT reuptake inhibitor - SSRI.
3. Pure 5-HT releaser (presynaptic)

Only indalpine made it to market, and that was exclusively in France. I dont know why it was discontinued, but my guess is that it was for a lack of efficacy in treating depression. It did have some anxiolytic effects, though. I found it to be a crappy antidepressant. It just made me yawn. Im not sure, but yawning might be a startup side-effect that emerges only during the first exposure to a SSRI. For the sake of accuracy, the first SSRI sold anywhere in the world was zimeledine (Zelmid). It was marketed in Sweden during the early 1980s. However, it was soon discovered that it precipitated Guillain-Barre Syndrome (GBS). This otherwise rare condition involves the damaging of the myelin sheath that surrounds the axons of certain kinds of neurons. In the brain, myelinated neurons comprise the white matter a grouping of high-speed cables that relay information (action potentials) between structures comprised of gray matter. To use a computer analogy, the gray matter is the processor and the white matter are the busses that carry the processed information to other sites. Zimelidine was withdrawn. The first SSRI approved by the U.S. FDA was fluoxetine (Prozac). Believe it or not, fluoxetine was synthesized based upon the pharmacology of diphenhydramine (Benadryl) in 1972. The FDA didnt approve fluoxetine until 1986.

Baron Shopsins go-to drug for treatment-resistant depression was clomipramine (Anafranil). Clomipramine was patented in 1963, and appeared around the world before the FDA in America would even consider it. Because it was unavailable in the United States prior to 1989, Shopsin had his patients order it from a Canadian pharmacy. (I used Paul Shore). Even so, the FDA has granted an official indication for the treatment for OCD. They considered it a me-too drug for depression, so OCD remains its only official indication. There was already a plethora of tricyclics available for depression. That is an incredibly plebeian act that has denied many people their only chance of attaining remission from depression.

I think an argument can be made that, of all the tricyclics, clomipramine is the most effective for both OCD and depression. In fact, clomipramine is used off-label for the following:

* Depression
* Anxiety
* Treatment-resistant depression
* Cataplexy syndrome
* Insomnia
* Neuropathic pain
* Chronic pain
* Body dysmorphic disorder
* Panic disorder
* Premature ejaculation
* Pediatric nocturnal enuresis
* Trichotillomania

One of the things that Dr. Shopsin did before moving to Indianapolis was to ask me to perform research for him. He intended to expose the unethical relationship between pharmaceutical companies and the FDA. He didnt have sufficient evidence, though. I found it. I had to spend hours poring over medical journals in the Rutgers medical school library. There was no Google back in late 1985. I doubt he would have listed me as co-author, though. His ego was too big (may he rest in piece). Shopsin said that I did better work than his medical school students at NYU, who were blessed with 170 IQ. My mistake was to tell him mine. At the time, I really didnt think 170 was stratospheric. I was genuinely naïve. Things between Shopsin and me deteriorated after that. One day, he said that he wasnt sure why I was so refractory to treatment. He went on to say that my receptors were f*ck*d-up. I doubt he thought that I would ever get well. I wish he were still alive. I would love to show him that he was wrong. When he left for Indianapolis, I was forced to find another doctor. On his last day, I chased him as he was pulling out of the parking lot with his Maserati. I was desperate for one last piece of advice from him. This was in early1986. He rolled down his window, and said but one word to me Periactin. Then he drove off. Periactin is cyproheptadine a drug primarily used as an antihistamine. However, its serotonergic actions were ignored for years. I never tried cyproheptadine, but my guess is that Shopsin thought its underappreciated serotonergic properties would help me.

I miss Baron Shopsin. He had a mind that was particularly well-suited to operate in a frontier of medicine that had very little scientific guidance to develop treatment principles. My access to him proved to be an invaluable resource to my future treatment decisions.

As an aside, Dr. Shopsin told me that lithium successfully treats neuroblastoma. That was in 1984. I didnt understand the significance of this at the time, but I never forgot what he said. I never looked into it until recently. I snickered and shook my head after performing a search on PubMed.

I subsequently found Malcolm Kaswan of Beth Israel. He was never a big name in the field. Despite this, he actually brought me very close to full remission by combining tranylcypromine (Parnate) 60 mg/day + desipramine (Pamelor) 150 mg/day. The combination was really harsh at first. My resting heart rate remained at 90 bpm throughout 9 months of treatment. Technically, tachycardia begins at 100 bpm, but I experienced heart palpitations nevertheless. It took about 2 months to approach remission once I began to see the first signs of improvement. Unfortunately, a delusional mania emerged after 6 months of a stable remission. The mania was predominantly dysphoric. It was not much fun. Kaswan had me discontinue treatment entirely. After exactly 2 months, I relapsed. Unfortunately, Prozac was approved by the time I saw Kaswan again. It was a new toy for psychiatrists.

After Prozac proved worthless to me, Kaswan refused to put me back on the drugs that got me well the first time. It made clinical sense at the time, though. However, the manic reaction to treatment might have been better treated by keeping Parnate and desipramine on board, and to try adding Depakote (valproate), which had been approved for epilepsy in 1983. Another accepted strategy at the time was to combine lithium and clonazepam, which has the most potent anticonvulsant properties among the benzodiazepines. I wouldnt have wanted to take Thorazine or Haldol, but those drugs would have been among the alternatives available. So, I was forced to resume suffering an anergic depression with psychomotor retardation and cognitive impairments. However, my depression was more severe. Eventually, I found another doctor willing to treat me with Parnate and desipramine. However, the treatment would never work again.

This is a lesson that should be heeded by everyone. For Gods sake, dont pulse antidepressants. If you have a history of TRD, for Gods sake, keep taking your medication regime indefinitely.

I would battle severe TRD for the next 33 years. However, I never allowed myself to even entertain the thought of committing suicide*. I would cut-off any thoughts that emerge that had the potential lead me in that direction. I never searched Google to find out the quickest and most painless method to kill myself. I knew that even this would leave me way too close to designing a plan and going through with it in as an act of impulse.

* I would like to introduce here the term I came up with, and that I find to be a more accurate depiction of a rational suicide performed by someone of sufficiently sound mind to end their suffering. Of course, this would exclude impulsive acts of desperation. To me, auto-euthanasia is a better fit.

Jeffrey Apter treated me between 1990 and 2000. He was an assistant professor at Princeton University. I was his patient between 1990 and 2000. He was the most aggressive psychopharmacologists that I had encountered to that point. He was very comfortable putting me on a combination of:

1.Parnate (tranylcypromine) - MAOI
2.Pamelor (desipramine) - TCA
3.Ritalin (methylphenidate -or- Dexedrine (amphetamine)
4.Parlodel (bromocriptine)
5.T4 thyroid supratherapeutic dosages.

Good luck finding a doctor who would be willing to replicate this treatment regime for you. I found only one more.

I once asked Dr. Apter what he thought of physostigmine well before it was approved to treat Alzheimers Disease. Physostigmine (Antilirium) is an acetylcholine acetylcholinesterase inhibitor, which is analogous to a MAOI, but spares acetylcholine rather a monoamine. I had been keeping up with Alzheimer's Disease and the advent of drugs to treat it since the early 1980s while I was researching my own illness at the Rutgers medical school library. Back then, Alzheimer's was a disease that not many people knew about. I remember thinking that it was a weird and hideous disease, but not at all common. I was fascinated and horrified at the same time, but I didnt feel people in general had anything to worry about. That was the consensus of experts at the time. Then, modern medicine helped people live into their 90s. This was a different situation entirely. I think that Aricept (donepezil) is the most often prescribed of these drugs. There are less than a handful of cholinesterase inhibitors. Namenda (memantine) plays the role of the go-to adjunct if Aricept monotherapy fails to work well enough. I really dont know why scientists thought that a drug that blocks NMDA glutamatergic receptors would be clinically useful. However, memantine might possess an as of yet undiscovered pharmacological property that may make it useful. Unfortunately, the consensus among neurologists today is that these drugs really dont work. Thats sad. My mother contracted Alzheimers Disease three years ago. She left us last February. The combination of Aricept (donepezil) and Namenda (memantine) was inert for her. However, Aricept caused her to lose her sense of taste, or made food taste different and unpalatable. This side-effect is called taste perversion. I had her doctor take her off both drugs. Perhaps her greatest pleasure was the taste of food. I refused to take this away from her when the drug that caused the taste perversion was useless.

Dr. Apter made a shift in his career as a clinical psychiatrist, and focused on Alzheimers Disease. He served to perform clinical trials of treatments to further our understanding and treatment of Alzheimers. I havent spoken to him in quite some time. However, I accidentally came across a video of his giving a lecture on Alzheimers on YouTube. He was describing the two substance anomalies that have been implicated in this disease beta amyloid protein and tau protein. I think we are close to having a blood test to screen for Alzheimers. It measures the amount of tau protein in the blood. Honestly, I dont think I would want to know.

I began taking lithium over 10 years ago. I experienced a very real, but mild improvement within 6 hours. After several months of taking an inadequate treatment regime, I decided to keep it onboard for only one reason. I wanted to reduce my risk of getting Alzheimers Disease. People with a history of unipolar or bipolar depression are *much* more likely to develop Alzheimers. There is a plethora of papers to be found on PubMed describing lithium as having the property of reducing the risk of getting Alzheimers. I first encountered the emergence of this information in the medical literature at least 20 years ago.

By the way, this prophylactic effect of lithium carbonate occurs at dosages far lower than the lowest dose pill available, which is 150 mg. I stuck with 300 mg/day because that is the dosage that produced the mild improvement. At low dosages, 300-450 mg/day, lithium usually does not produce any long-lasting side effects. There will likely be some mild psychiatric side effects, including sedation, brain fog, and passivity (not to be confused with apathy). These are the things that will probably disappear by 2 weeks. Musicians and painters hate being on lithium. As a research patient at the NIH, which Dr. Apter facilitated for me, the department I was in was run by William Z. Potter. The team performed investigations that included healthy volunteers. One such investigation included giving lithium to healthy volunteers. One of them was a musician. During a conversation I had with him one night, he told me that he all of a sudden lost his creativity, and was upset about it. He couldnt figure out where it had disappeared to. I had to bite my tongue. I didnt know whether or not he was in a blinded investigation. Obviously, he was chosen to take lithium. I imagine he was euphoric when he experienced a sudden surge of inspiration after the investigation concluded and he went home.

Why do I need 300 mg/day of lithium to produce an improvement in my bipolar depression when I relapse at 450 mg/day? (Lithium also works for unipolar depression, but is most often used as an adjunct to antidepressants.

I fail to respond to lithium @ 150mg/day
I remit @ 300 mg/day
I relapse @ 450 mg/day

This following is a summary of my hypothesis that there is connection between the bimodal (biphasic) pharmacological activity of different dosages of lithium and its clinical activity. It is difficult for me not to suggest that most people with depression or bipolar depression (in the absence of mania or ultra-rapid cycling) try low-dosage lithium at some point. My guess is that 300 mg/day is the sweet spot, but I imagine some people will need 450 mg/day. Maybe a range of 150 mg/day to 450 mg/day is a valid dosage range. Lithium blood levels are irrelevant.

Low dosages = Treats depression.
Low dosages = Increases glutamate release.
Low glutamate activity is associated with depression.

High dosages = Treats mania, bipolar prophylaxis, reduces rapid-cyclicity.
High dosages = Reduces glutamate release.
High glutamate activity is associated with mania.

I felt a sense of urgency to convey to Psycho-Babble what I had learned from true experts along my journey. Once I responded to treatment, I had access to the memories of my treatment history and the insights contained in the first two generations of psychopharmacologists. I listed many of them by name here. I was finally able to put together the knowledge, experience, and clinical gems that were taught to me by these people. In 1992, while I was at the NIH, I began to witness what seemed to me to be the beginning of the loss of the clinical insights of those doctors who treated me a decade earlier. If a doctor refuses to use a MAOI after three failed trials of other drug treatments, look for help elsewhere. A willingness to prescribe MAOIs is my litmus test for choosing a doctor.

Too many people on Psycho-Babble appear to disallow their medical doctors to help manage their treatment closely enough when taking such powerful drugs. I dont see this in everyone, of course. I am in no ones shoes but my own, so I have no idea what challenges other people have to overcome in order to find competent doctors. I sometimes wonder how many of people here use general practitioners for their care. Psychiatrists are a dying breed, and good ones are often impossible to find locally.

* NO DOCTOR would ever contemplate prescribing Effexor, or any other available antidepressant, for intermittent use as a palliative treatment (PRN). The first important piece of expert advice that I received came from the Columbia Presbyterian depression research department. They advised me to avoid pulsing antidepressants. Of course, this is something seen commonly on Psycho-Babble.

* NO DOCTOR would keep giving their patient the same drugs over and over again and expect different results. I know that the efforts of every single member of Psycho-Babble are brave and noble. They demonstrate great compassion and altruism. However, they also demonstrate a woeful lack of education and insight regarding the *clinical* applications of the information they find on PubMed. Remission is not found in knowing how histones are affected by lithium so as to effect neuroprotection, especially in neurodegenerative diseases.

My advice is that you spend more time researching clinical methods of treatment that result in remission rather than researching the role of adenyl cyclase in producing second-messenger cascades. Pay attention to the old along with the new. Lamotrigine was approved by the FDA in 1996. The rest of the drugs used in my successful treatment regime were available by 1970. Thats a bitter pill to swallow no pun intended.

All of the drugs that I am currently responding to were available in 1996. I was 36 at the time. Thats a bitter pill to swallow no pun intended.

I tried lamotrigine as soon as it was approved. Why? Because the seizure disorder unit at the NIH told the both the biological psychiatry department and the clinical pharmacology departments that a whole bunch of their patients taking lamotrigine reported that their depression improved dramatically while taking their investigational drug. Their improvement was probably short-lived, though. They didnt tell my unit that, but this was probably because their patients hadnt been treated with lamotrigine for long enough when they reported the phenomenon to Dr. Potter. It doesnt appear to me that lamotrigine is terribly effective as monotherapy. One thing I found with me is that lamotrigine does not follow an all-or-nothing pattern of response. 200 mg/day helped quite a bit. 300 mg/day helped me quite a bit more.

I struggled with pain and frustration for another 24 years. 36 would have been a great age to wake up and experience normal consciousness again. Finally, at age 60, I was freed from the bondage of bipolar depression. I doubt very much that I would have found remission by using Effexor periodically for a few days at a time as some sort of palliative PRN, or never taking an antidepressant for more than 2 weeks. To do this is absolutely insane. This would have been immediately obvious to the doctors who I had the privilege to be treated by or who I consulted with. They were some of the best minds in the field.

SMART: To achieve remission, I used a strategy that I have already described on Psycho-Babble numerous times. I wont bother describing it again.

LUCK: Over ten years ago, I decided to continue taking lithium in order to reduce my risk of getting Alzheimers Disease. I used 300 mg/day for prophylaxis. Dosages of lithium far lower than this have been reported as being effective. So, it turns out that had I not been taking lithium in the background to prevent Alzheimers, I would never have achieved remission.

Sometimes, serendipity plays a role that is just as important as the decisions made by your doctor.

For those of you who want to enhance your chances of finding a successful treatment for your treatment-resistant depression, you might find some value in what I have written over the last few weeks. If you are not receptive to it now, perhaps you will be a year from now. I recommend that you go back and find my posts from the last few weeks and copy them to your computer. This isnt a self-serving, grandiose demonstration to feed an insatiable ego. It is entirely altruistic. Believe it.

I havent decided whether or not to post on the board anymore. If anyone wants to converse with me, you can use Babblemail. I wont tell.

* The bottom line is that I learned from the first two generations of psychopharmacologists. I doubt there are too many people here on Psycho-Babble who were a part of the advent of biological psychiatry. If so, I hope they weigh in.

If Im wrong about everything, I apologize in advance. I suppose its possible. Its not 1983 anymore. You can use Google to appraise the accuracy of this treatise and begin a rational approach to continuing your extraordinarily painful odyssey. As Ive said, I cant guarantee that anyone will respond to treatment using my suggestions. However, I can all but guarantee that no one will respond to what most of you are doing now.

By the way, in 1983, after attacking the medical school library for 2 weeks while in an improved state, I came back to my doctor at Columbia Presbyterian to inform her that I had come to think than maybe MY problem involved a lack of dopamine. After coming to that conclusion myself, I discovered that there was only one author in the medical literature that I could find who had come to the same conclusion. His last name was Randrup. I dont remember his first name.

Anyway, I told the doctor that I had several dopaminergic drugs that I was interested. The one I wanted most was Wellbutrin, which was investigational at the time. I then told her that bromocriptine would be my second choice. My doctor actually looked me in the eye and laughed. She said, Well yeah, if you want to throw up all day long. She later went on to Pfizer to oversee their clinical trials of Zoloft (sertraline). I doubt very much she forgot me or that conversation. About a year later, I met her in Manhattan while I was walking uptown and passing the hospital. She was playing with Vitamin B6, hoping it would improve PMS / PMDD. It didnt.

Hard to believe, right? 1983? Me? Dopamine? They were still stuck on norepinephrine at the time. I would say I was at least a decade ahead of the curve. Right? I cant find my notebook containing the evidence and thought processes. Ive looked all over for it. I apologize.

When I left Dr. Apter, I asked him for recommendations. He gave me two names. The first one was another notable researcher in Manhattan. The second was a local practitioner. I figured that since big names had failed me in the past, I would try the local guy.

My successful treatment is the consummation of a very long and arduous journey that included some of the best psychopharmacologists in the world. I had access to them because I live so close to Manhattan. The wisdom they gave me is my gift to you. Use it.

Some see things as they are and ask why.
I dream of things that never were and ask why not.

The only thing necessary for the triumph of evil is that good men do nothing.

This might be my last post on Psycho-Babble

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