Receptor downregulation, Tolerance & Neuroprotective?

[cloudmonger]

I know there are some amateur pharmacologists here... a question along the topic of neuroplasticity. I've heard that chronic use of antidepressants can eventually "downregulate" your receptors (Serotonin I'm assuming) so that if you ever come off the drug, your brain will never be the same as before, it will never function the same without the med, because your brain adapted/changed due to the medication (or become dependent to function in some way)...

I'm wondering if the same thing happens with Stimulant drugs? I'm aware that tolerance builds up if you use them everyday for a year or more, however, what if you use stimulants for 6-9 month periods, then take breaks?

Is there a proven way to avoid both the tolerance issue and this receptor "downregulation"? I'm also wondering if ALL psych drugs cause dowregulation of receptors if used everyday for long periods (I've heard the opposite also, like some drugs are neuro-protective)? Can you ever recover (i.e. if you are someone that uses psych medications on an episodic basis)?

 

Edited October 29, 2016 by cloudmonger

[Wooster]

One of the principle tenets of neural plasticity is that the brain adapts to changing conditions. This means that if you allow yourself enough time, your brain will eventually go back to its baseline. For example, we used to think that the brain changes seen in meth abuse and addiction were permanent. That no longer appears to be the case.

The question is, though, why set your brain back to baseline if you were medicating it in the first place?

[Cerberus]

Cloudmonger - If there were a proven way to avoid the tolerance issue, there would be a proven way to avoid the addictiveness "issue". Clearly, there is not. The safest course for long-term use is to follow the prescriber's instructions dosages and instructions exactly, as these will be formulated to avoid the problems to the greatest degree possible. I might add that there are no "amateur pharmacologists" here on CB - we strive to be active in our own treatment in partnership with our treatment professionals, and take the time to study and learn about our conditions and the medications used to treat us so as to be better informed. We do not diagnose, we do not attempt to prescribe, and we call people on their shit if they do. Anyone who posts what sounds like science-based fact on this site had better know his or her apples, because we'll know it if they don't.

[Wooster]

(for example, in re the claim I made that meth abuse brain loss and cognitive function may actually repair rather than continue to be lost https://www.ncbi.nlm.nih.gov/pubmed/19339145/)

[notloki]

But if you are taking this med as prescribed there will be no damage done.

[cloudmonger]

4 hours ago, Wooster said:

One of the principle tenets of neural plasticity is that the brain adapts to changing conditions. This means that if you allow yourself enough time, your brain will eventually go back to its baseline. For example, we used to think that the brain changes seen in meth abuse and addiction were permanent. That no longer appears to be the case.

Thank you Wooster - this sort of answers my question. I guess given the brain has "neural plasticity" it can change....I was not aware that with meth addiction the brain eventually is able to ever get back to normal functioning. My question is NOT around abusing medications or drugs (or taking more than prescribed) I guess my question was more around, at what point do psych medications permanently change the brain & make it dependent on the medication? Are these meds really meant to be taken for life?

Please don't flag me as "anti-med" which i am not. I'm trying to understand how it all works, and like to consider all perspectives (including those of skeptics like Robert Whitaker and Daniel Amen). They do NOT claim that medications have no value and that no one should take them. They acknowledge that many people benefit from psychopharmacology, especially over the short term.. Over time, Whitaker argues, drugs make many patients sicker than they would have been if they had never been medicated.

An excerpt from Scientific American:

https://blogs.scientificamerican.com/cross-check/are-psychiatric-medications-making-us-sicker/

Whitaker compiles anecdotal and clinical evidence that when patients stop taking SSRIs, they often experience depression more severe than what drove them to seek treatment. A multi-nation report by the World Health Organization in 1998 associated long-term antidepressant usage with a higher rather than lower risk of long-term depression. SSRIs can cause a wide range of side effects, including insomnia, sexual dysfunction, apathy, suicidal impulses and mania--which may then lead patients to be diagnosed with and treated for bipolar disorder.

Indeed, Whitaker suspects that antidepressants—as well as Ritalin and other stimulants prescribed for attention deficit disorder—have catalyzed the recent spike in bipolar disorder. Relatively rare just a half century ago, reported rates of bipolar disorder have spiked more than 100-fold to one in 40 adults. Side effects attributed to lithium and other common medications for bipolar disorder include deficits in memory, learning ability and fine-motor skills. Similarly, benzodiazepines such as Valium and Xanax, which are among the drugs prescribed for anxiety, are addictive; withdrawal from these sedatives can cause effects ranging from insomnia to seizures, as well as panic attacks.

Whitaker’s analysis of treatments for schizophrenia is especially disturbing. Antipsychotics, from Thorazine to successors like Zyprexa, cause weight gain, physical tremors (called tardive dyskinesia) and, according to some studies, cognitive decline and brain shrinkage. Before the introduction of Thorazine in the 1950s, Whitaker asserts, almost two thirds of the patients hospitalized for an initial episode of schizophrenia were released within a year, and most of this group did NOT require subsequent hospitalization.A long-term study by Martin Harrow, a psychologist at the University of Illinois, found an inverse correlation between medication for schizophrenia and positive, long-term outcomes. Beginning in the 1970s, Harrow tracked a group of 64 newly diagnosed schizophrenics. Forty percent of the non-medicated patients recovered—meaning that they could become self-supporting--versus five percent of those who were medicated. Harrow contended that those who were heavily medicated were sicker to begin with, but Whitaker suggests that the medications may be making some patients sicker.

[thunder]

Initially, when I was 19/20 and considering medication, I worried about the long term effects of medication and whether or not I would have to be on medication for the rest of my life.I tried doing therapy only for about 6 months, but saw little positive effect. Eventually, I reached the conclusion that, for med, medication was necessary for me to continue functioning day-to-day. Over time, I realized that worrying about possible long term effects was silly, because without medication, I would have no long term. I was sporadically suicidal since my early teens, as well as periodically had sufficient difficulty functioning that I would have been worried about my ability to finish school or hold a job. I'll take problems down the road if it means a better quality of life until I get there. Likewise, even though I've had to switch medications several times (crossing fingers that my pdoc is correct and lamictal will work longer tem for me), I no longer seeing being med-free as a realistic goal, so I don't care about whether medications will make my unmedicated state worse. 

One thing that I have heard is that for people with mild to moderate depression, SSRI's may be less effective, and these people may have better results with therapy alone. If you can function alright without medication, it seems reasonable to critically examine whether medication has more risks than remaining untreated (all medications, psychiatric or otherwise have some risks, so considering whether these risks are worse than leaving a condition untreated is always good practice). But if your symptoms are unbearable and make functioning difficult to impossible, in my mind, it is worth taking the more risks when it comes to risks that are either relatively rare or relatively distant in the future.

[jt07]

I would be dead without meds, and I'm not kidding myself that my current cocktail is the reason that I have gotten some joy back to my life that I have not felt since childhood. I will remain on meds probably for life and, like thunder, I'm not worried about possible theoretical effects that have not been proven in a large swathe of living human patients. I value my life and my happiness more than that.

[Velvet Elvis]

Downregulation is reversible and actually the key mechanism of action for SSRIs IIRC.

I'd be able to dig up more and give a much better response were I not currently off meds myself.  

This is also on entirely the wrong board, moving.

 

[cloudmonger]

5 hours ago, Velvet Elvis said:

Downregulation is reversible and actually the key mechanism of action for SSRIs IIRC.

thanks everyone...I'm trying to learn more and figure out what to do. I've been discouraged after trying so many meds for years, then having to spend time trying to taper off/dealing with withdrawals, side effects. I wasn't feeling noticeably BETTER on them.

I have bouts of bad periods but I've learned to keep telling myself "this soon shall pass" over time so the severe moods don't last as long (NOT to say my depression is only mild) however, I'm having huge doubts that meds will greatly improve my quality of life or bring me any "Joy"....I was told in Therapy that meds can only do so much - I don't know if they can pull you out of chronic apathy/negativity...they are by far not "Happy" pills (in my experience) but I suppose they can make you more stable, manage some symptoms, help you get out of bed, put one foot in front of the other, so it's a small start in the right direction.

I worry about getting back on the medication rollercoaster and then never being able to come off or have my brain adjust. I worry about the meds adding more psychological or physical problems that could destabilize me and make me worse. Sorry to post here, didn't know the most appropriate section...

[OliverB]

There are meds than easily can cause life long conditions if you take them the wrong way, like a really heavy dose of an antipsychotic leading to permanent tardive dyskinesia, metabolism syndrome  and it consequences (diabetes, hypertension, ...) or cognitive impariments. Or if you take more than two SSIR at high dose and you get serotonin syndrome. Or lithium toxicity if you don't do your blood test and it goes too high it can damage your cerebellum permanently. Or if you take a high dosage of benzodiacepines everyday, you are likely to become dependant to it and get side effects like confusion, memory impariments, poor moto coordination, ...

The key? Take only what you need, when you need it and the lower dose you need, and remember meds don't cure anything, there is a large part you have to do by your own (excercise, healthy diet, mental excercise or mind training -It includes playing chess, a music instrument, studying, reading-, do something artistic -painting, writing, coloring-, psychotherapy ...), mainly to avoid the toxic stress that worse all conditions and to have 'possitive' experiences  that make your brain release neurotrasmisors that make you happier and more stable.

AD never helped me with my depression, atypical antipsychotic either, lamictal it's preventing me from cycling but I am still depressed (not that bad as before, but still). Now I am not that bad thanks to Lamictal I can force myself to some activities that improves my mood and self-streem. It's hard and it's not a cure, but meds aren't 100% a cure either, I think they are there to help you to make your first step when you are in a so bad situation you can't do anything to improve by your own.

[JustNuts]

For most psych meds, any changes are largely or entirely reversible. Notable exceptions are methamphetamine in any dose (directly neurotoxic), extremely high recreational doses of amphetamine (possibly neurotoxic), lithium (long term therapy usually leads to severe thyroid issues and possible kidney function issues, among others), and antipsychotics (can cause permanent tardive dyskinesia). Drug tolerance is a complicated subject. Tolerance to some extent is a normal feature of drug therapy, only tolerance leading to a sudden lack of therapeutic benefit is clinically relevant. Solutions for drug tolerance include increasing the dosage, changing the medication, and (in the case of ADHD meds) potentially taking short breaks from the medication (although current clinical best practice guidelines strongly suggest that this is a controversial practice that may have more negative than positive effects and should be used only on a case-by-case basis). In many cases, tolerance does not develop to a clinically significant extent.

The claim that antipsychotics induce permanent changes in brain structure or function is controversial and considered dubious in most published scientific literature on the subject.

Some very weak evidence suggests that benzodiazepines may lead to cognitive decline later in life.

According to the current scientific literature, antipsychotic-induced metabolic syndrome is almost exclusively a consequence of increased appetite and subsequent weight gain (which is not inevitable and is merely a consequence of failing to handle the increased appetite appropriately). There is very limited evidence suggesting that antipsychotics may directly contribute in a limited way to metabolic syndrome in conjunction with the indirect appetite->weight gain link, but there is no evidence to support a claim of antipsychotics being capable of inducing permanent metabolic syndrome directly, only indirectly via the appetite->weight gain link (as overweight/obesity is the primary cause of metabolic syndrome, and weight gain as a result of increased appetite will persist even after antipsychotic discontinuation).

On the topic of SSRI discontinuation - this is a controversial and misrepresented subject. Reemergence of depression after antidepressant discontinuation is considered by many psychiatrists to merely be the resurgence of underlying depression that was being successfully treated by the antidepressant. Other SSRI discontinuation side effects are generally not disputed, but a large number of side effects popularly attributed to SSRI discontinuation are not supported by the scientific evidence on the subject, while some extremely rare side effects are often misrepresented as being much more common than they actually are.

Induction of mania from SSRIs is generally considered to be an indicator of bipolar disorder, although a limited number of clinicians may view it as substance-induced mania instead. The risk of suicidal ideation/impulses/attempts from SSRI treatment is considered to be a rare side effect except in children and adolescents, who should generally only be treated with fluoxetine due to its significantly lower risk of suicidal ideation/impulses/attempts in this population, although other antidepressants can still be considered as second-line treatments depending on the severity of the depression.

The potential for drug addiction exists with stimulants and benzodiazepines. It also exists to a much lesser extent with α2δ ligands and α₂ adrenoceptor agonists. However, there is a risk-benefit equation with every medication's use for any particular condition. Addiction is not a given side effect of taking these medications, it is merely a possible one. In the case of stimulants, the potential for drug addiction is high enough that the risk-benefit equation is only considered favorable in a few limited cases, primarily ADHD and narcolepsy. In the case of benzodiazepines, the risk-benefit equation is only considered favorable for certain cases of anxiety, seizures, sedation, induction of sleep, etc. In the case of α2δ ligands, the risk is relatively low, so addiction is not much of a factor. In the case of α₂ adrenoceptor agonists, the risk is extremely low, so addiction isn't considered a significant factor.

Only a small percentage of people who take an addictive drug will become addicted. The risk increases dramatically if the drug is intentionally not taken as prescribed. For some people, addiction to certain drugs is highly likely. However, many people are perfectly capable of taking addictive drugs as prescribed without abusing or misusing them.

Drug dependence is a different issue entirely. It is very complex in nature, and often considered a non-issue on a broad scale. The only notable exception to this is benzodiazepines, but a slow titration is standard clinical practice and eliminates the significant risk associated with sudden withdrawal of benzodiazepines.

Poorly-constructed conspiracy theories that psychiatric medication makes the disorder worse are pure ignorant idiocy at its finest and are contradicted by literal mountains of scientific research. The introduction of psychiatric medication has had an incalculably large positive effect for countless millions of people whose prior options were primarily lobotomy and/or institutionalization. The Oxford Textbook of Community Mental Health has some excellent information on just how huge of a change this was for the mentally ill.

[jt07]

5 hours ago, cloudmonger said:

thanks everyone...I'm trying to learn more and figure out what to do. I've been discouraged after trying so many meds for years, then having to spend time trying to taper off/dealing with withdrawals, side effects. I wasn't feeling noticeably BETTER on them.

I have bouts of bad periods but I've learned to keep telling myself "this soon shall pass" over time so the severe moods don't last as long (NOT to say my depression is only mild) however, I'm having huge doubts that meds will greatly improve my quality of life or bring me any "Joy"....I was told in Therapy that meds can only do so much - I don't know if they can pull you out of chronic apathy/negativity...they are by far not "Happy" pills (in my experience) but I suppose they can make you more stable, manage some symptoms, help you get out of bed, put one foot in front of the other, so it's a small start in the right direction.

I worry about getting back on the medication rollercoaster and then never being able to come off or have my brain adjust. I worry about the meds adding more psychological or physical problems that could destabilize me and make me worse. Sorry to post here, didn't know the most appropriate section...

Indeed, meds can only do so much. But it sounds like in your case meds weren't doing anything at all. I have struggled with depression and anxiety since at least 12 years old. It was only in the last 10 years that I found an effective cocktail that actually works. The rest of my life was spent trying antidepressant after antidepressant to no effect. It turns out that antidepressants don't affect me much other than help anxiety. I've had much better luck with the atypical antipsychotics and the anticonvulsants. 

If you ever get on a med or med cocktail that works, you will know it. There will be no doubt. Can meds do everything? No. You have to change depressive behavior. But meds can get your mind into a place where it can start to make the changes.

[Cerberus]

Also, perhaps unnecessary to say, but because it's pretty much what we remind everyone around here - Have this conversation with your psychiatrist.

[notloki]

On 10/30/2016 at 6:00 AM, JustNuts said:

For most psych meds, any changes are largely or entirely reversible. Notable exceptions are methamphetamine in any dose

Not true. Amphetamine and methamphetamine are only neurotoxic at high doses only. The has been demonstrated by multiple animal studies. People take methamphetamine as a prescribed drug (Desoxyn) for narcolepsy and sometimes ADD. 

Edited November 5, 2016 by notloki

[JustNuts]

On 11/1/2016 at 3:30 PM, notloki said:

Not true. Amphetamine and methamphetamine are only neurotoxic at high doses only. The has been demonstrated by multiple animal studies. People take methamphetamine as a prescribed drug (Desoxyn) for narcolepsy and sometimes ADD. 

Methamphetamine is well known to be neurotoxic irregardless of dose. At extremely high doses, amphetamine appears to become neurotoxic, but it is definitely not neurotoxic in regular doses.

[toast]

t

Edited April 17, 2017 by toast

[notloki]

Emsam over here. deprenyl (selegiline) does not produce much methamphetamine but I have heard of ppl having trouble sleeping.