Antidepressant effect of D3 preferring dopamine agonists

[MeDieViL]

This is a few of many references as requested in another thread, d3 agonism is responsible for the antidepressant effect, d3 preferring agonists however have side effects such as compulsive gambling is 20% of perkansin patients, there are reports of grandpas suddenly wanting anal sex, they are good to give to girls, if youd like ropi or whatever for sexual reasons suggest it to a girl for that reason, its a good tool as it enhances the experience.

Dopamine is implicated in depression for a large part while sero isnt but i havent got the time to go into that, thats one of the reasons some ppl with depression would do well on my intervention of memantine with dexamphetamine, for the long term treatment of depression, which cant work according to most, which havent tried offcourse

the reason they cause gambling is according to one theory because they impair normal reward, which imo can be counteracted with the addition of a stim to shift dopaminergic balance, again i have no time to get into that.

This drug has come up before on M&M, but some recent studies have considerably added to the amount of data available on the drug.

First of all, pramipexole is a non-ergoline dopamine D2/D3 agonist. It does not have the heart valve damage issues that its cousins cabergoline (Dostinex) and bromocriptine have. It also displays, somewhat interestingly, a higher affinity for D3 than D2, in contrast to bromocriptine (almost purely D2) and cabergoline (mixed D1/D2). It's Rx (non-scheduled) in the U.S., and studies are appearing about the drug at an impressive rate.

From personal experience, it has remarkable libido- and erection-improving capabilities and may indeed have some antidepressant properties, though I'm still testing the drug myself.

At any rate, the following make for some very interesting reading.

Major Depression In (PMID 10812530), (PMID 12479663), (PMID 15219473), and (PMID 14992985) pramipexole was tested as a lone antidepressant (first study), as an adjunct to an antidepressant (second study), or as an adjunct to a mood stabilizer (third and fourth studies). In all four, it showed considerable efficacy in major depression or bipolar depression. The first is probably most interesting, as it showed (relatively) high-dose pramipexole alone may be as effective as fluoxetine in the treatment of MDD.

Synergy With SSRIs In (PMID 16963794), data suggests that not only is pramipexole effective as an antidepressant, but it may actually synergize with SSRIs (at least setraline and fluoxetine) in a fairly interesting way. (See the study for details.)

Mechanism The study (PMID 18688211), though in rats, is probably the most interesting I've found. I'm going to simply quote the last portion of the abstract:

<div class='quotetop'>QUOTE </div><div class='quotemain'>After 14 days of PPX treatment, the firing rate of DA had recovered as well as that of NE, whereas the firing rate of 5-HT neurons was increased by 38%. It was also observed that sustained PPX administration produced desensitization of D(2)/D(3) and 5-HT(1A) cell body autoreceptors, as well as a decrease in sensitivity of alpha(2)-adrenergic cell body autoreceptors. These adaptive changes are implicated in long-term firing rate adaptations of DA, NE and 5-HT neurons after prolonged PPX administration. In conclusion, the therapeutic action of PPX in depression might be attributed to increased DA and 5-HT neurotransmission.</div>

In short, though pramipexole is a D2/D3 agonist, it rather dramatically increased the firing rate of 5-HT neurons and desensitized 5-HT(1A) and D2/D3 autoreceptors. The implication is that it should, with chronic use, improve D2 and 5-HT1A sensitivity and increase 5-HT neurotransmission. As all three of these factors have been implicated in major depression (among other psychiatric disorders), this seems absolutely enormous. And note that this study is from 2009, so it's implications have not yet filtered out.

This is pretty cool stuff. If it pans out, antidepressant sexual side effects may mean something very different a few years down the line...

EDIT: One last rather important detail. If you read the drug's entry on rxlist.com, it does not have many serious side effects, especially when the dose is titrated appropriately. (If you're going to try the drug, you really have to start at 0.25-0.5mg 2x/day and move up from there.) From personal experience, I got a little orthostatic hypotension, a little fatigue, and a little nausea at the start, but with continued treatment they went away. The last study in mice supports this - NE function declines initially, but recovers with chronic treatment. Fucking awesome.

 

[MeDieViL]

As an aside lemon essential oil a d1 antagonist induces torture in me, it makes my anhedonia worse, also aps that strongly block d1, block the anti anhedonia effect of stims, so i hypothise d1 is implicated in reward, d2 and d3 antagonism blocks the ability of stims to abolish my sa, which again is explained by plenty of research i will post later.

 

[sekio]

lemon essential oil a d1 antagonist

lemon oil is mostly just terpenes, there's not d1 antagonists in that

 

[MeDieViL]

I will look up the reference tomorrow after my manic episode, but i can guarantee you its the case, i beleive tea tree oil is simular.

 

[MeDieViL]

http://www.ncbi.nlm.nih.gov/pubmed/16780969

Apomorphine reverses its relaxant effect, there you go, i beleive its significant as when i take it when im anhedonic i go in severe agitation and suffering, and also d1 blocking aps block the anti anhedonic effect of stims,

I only post here when im manic but i do know what im talking about mate, just ask me for a ref, i never claim something without having references which doesnt mean they cant be disputed, im allways open for discussion and admit when im wrong, i wllways come off like i think i know best and see ppl sometimes avoiding discussing with me which is a shame, but then again i should try to post here when not manic lol.

 

[theGirlWithBlueHair]

I know the D1 and D2 receptors work synergistically with each other in parts of the brain, but I don't think that selective D1 antagonism will completely block the anti-amotivational and anhedonic effects of non-agonist dopaminergics, especially releasing agents, which aren't subject to autoreceptor control. The D2/D3 ligands ameliorate these symptoms, and they inhibit dopamine release from presynaptic neurons, functionally decreasing D1 activation. Yeah, the D3 receptor can cause some rather strange effects related to reward and motivation, as well as obsessive and compulsive symptoms, upon activation. Here's more about it:

http://www.hindawi.com/journals/pd/2012/603631/

[h=4]Abstract[/h]The dopamine agonists ropinirole and pramipexole exhibit highly specific affinity for the cerebral dopamine D3 receptor. Use of these medications in Parkinson’s disease has been complicated by the emergence of pathologic behavioral patterns such as hypersexuality, pathologic gambling, excessive hobbying, and other circumscribed obsessive-compulsive disorders of impulse control in people having no history of such disorders. These behavioral changes typically remit following discontinuation of the medication, further demonstrating a causal relationship. Expression of the D3 receptor is particularly rich within the limbic system, where it plays an important role in modulating the physiologic and emotional experience of novelty, reward, and risk assessment. Converging neuroanatomical, physiological, and behavioral science data suggest the high D3 affinity of these medications as the basis for these behavioral changes. These observations suggest the D3 receptor as a therapeutic target for obsessive-compulsive disorder and substance abuse, and improved understanding of D3 receptor function may aid drug design of future atypical antipsychotics.[h=4]1. Introduction[/h]An association between neurodegeneration of the dopaminergic nigrostriatal system and the major motor symptoms of Parkinson’s disease (PD) was first recognized in 1960 [1] after pioneering work by Arvid Carlsson showed that L-DOPA reversed the parkinsonian syndrome in rabbits induced by reserpine [2]. This observation led to the first trials of injected levodopa (L-dopa), a direct metabolic precursor of dopamine, to address motor symptoms associated with the disease. This treatment demonstrated transient success, but was impractical due to severe toxicities associated with the injections. Gradual titration of oral L-dopa was better tolerated, but was still associated with severe nausea and the requirement of higher doses of L-dopa due to peripheral consumption of the substrate. In the 1970s, compounding L-dopa with the peripheral dopa-decarboxylase inhibitor carbidopa very successfully addressed these shortcomings. Nausea and vomiting were reduced to such a degree that the medication adopted the trade name Sinemet (sine = without; emet = emesis). Compounded levodopa-carbidopa remains the mainstay of treatment for PD.Dopaminergic agonists are synthetic analogues of dopamine. Apomorphine was suggested for the treatment of PD as early as 1884 [3], although the first article describing its effectiveness was not published until 1951 [4]. Bromocriptine was found to be effective in PD in 1974 [5]. Other ergotamine dopamine agonists including lisuride, pergolide, and cabergoline were subsequently found to be effective. In the 1990s, two nonergot dopamine agonists (DA), pramipexole and ropinirole, were granted approval for use in the United States. These have been adopted by many clinicians for a variety of reasons, including a more stable motor response, improved side-effect profile, and more convenient dosing schedule.As DA medicines became widely used, unanticipated reports of poorly modulated risk taking began to emerge, and the link between these behaviors and the medications was recognized by the year 2000 [6, 7]. These took the form of compulsive gambling, hypersexuality, hyperphagia, and even hobbying or shopping that took on an obsessive-compulsive-type character. Examining the pharmacology of these medications and their specificity to the D3 dopamine receptors provides an opportunity to understand why these pathological behaviors are not generally seen with levodopa, why tardive movement disorders arise in many patients taking typical (dopamine-targeting) neuroleptics, and why the recognition of DA-agonist-related pathological behaviors in PD patients may suggest potential therapeutic targets for similar behavioral problems that arise spontaneously in the general population.[h=4]2. Dopamine Receptors, L-Dopa, and Dopamine Agonists[/h]Dopamine receptors have been divided into 5 different subtypes (D1–D5). Structurally, the D1 and D5 receptors are very similar, while the D2, D3, and D4 receptors are different from them. In particular, the D3 receptor has strong representation in the limbic system and its connections in the ventral striatum and is associated with cognitive, emotional, and endocrine functions [8].L-dopa increases the availability of dopamine in the brain, without known specificity for a dopamine receptor subtype. In contrast, the dopamine agonists ropinirole, pramipexole, and pergolide exhibit high affinity for the D3 receptors [9–11]. The older dopamine agonist, bromocriptine, does not share this specificity and appears to have greater affinity for the D2 receptor [9].This receptor specificity may have functional relevance to the increased rates of pathological behaviors, as the D3 receptor expression is particularly rich in limbic areas and often being coexpressed with D2 in regions serving sensory (sensory thalamic nuclei), hormonal (mammilothalamic tract), and association (amygdala) functions [12]. The D3 receptor appears to control the phasic, but not tonic, activity of dopaminergic neurons which may be induced by novelty or presentation of drug-conditioned cues in rodents [13–15]. These data seem to converge on an important role for the D3 receptor in modulating the physiologic and emotional experience of novelty, reward, and risk assessment and likely explain the relatively higher rates of pathological behaviors among patients taking DAs. Pathological behaviors associated with bromocriptine have not generally been observed, with a single case report in 2003 being the first time this association was noted [16]. This likely reflects the lower frequency of use and may also be understood in the context of bromocriptine lacking the D3 specificity of the more commonly utilized DAs. Animal models suggest that D3 receptor stimulation is also involved in the emergence of dopamine-induced dyskinesias [17, 18].[h=4]3. Pathological Behaviors[/h]The most commonly reported pathological behaviors have been pathological gambling, hypersexuality, compulsive or binge eating, and compulsive shopping. Uncertainty remains regarding the overall frequency of DA-associated behavioral changes. Initial surveillance suggested very low rates—on the order of 2%–8% [19]. Subsequent structured-questionnaire ascertainments found higher rates, with a recent large questionnaire-based assessment reporting a rate of 13.6% [20]. This cross-sectional study assessed rates of pathologic gambling (9.9%), compulsive sexual behavior (4.4%), compulsive buying (7.2%), and binge eating (5.6%) among current DA users, with a total of 17.1% of current DA users exhibiting any pathological behavior. This compared to the significantly lower rate of pathological behaviors (6.9%) among subjects not using a DA for at least 6 months prior to enrollment.Some authors argue that reliance on impersonal questionnaires or spontaneous patient reports likely results in incomplete ascertainment due to the sensitive and/or potentially embarrassing nature of these symptoms. Another recent report utilized physician-directed symptom elicitation and found pathological behaviors in 24% of patients using DA at therapeutic doses and in 30% of patients using “target” DA dosing [21]. Although involving a smaller population than some other reports, this paper highlights some difficulties in capturing behavioral changes with several patients exhibiting compulsive hobbying or computer use, and others having poor insight into their behavioral changes including a patient with compulsive gambling who perceived his behavior as “beneficial” due to net wins.Emergence of pathological behaviors is very uncommonly seen among patients treated with L-dopa alone [22]. A large study utilizing structured interview assessment found pathological behaviors in 6.9% of subjects not currently taking a DA, although prior exposure to DA was not reported [20]. In previous reports, the DA with highest D3 affinity (pramipexole) appears to be more commonly implicated in pathological behaviors both in PD and in restless legs syndrome [23], but a large cross-sectional study found no difference between current use and risk for pathological behaviors between DAs [20]. Again, prior DA exposures and reasons for discontinuation were not reported.The relationship between deep brain stimulation (DBS) of the subthalamic nucleus (STN) and impulse control disorders is complex, and it is the focus of several review papers [24, 25]. In general, a reduction in dopaminergic medication is seen after STN DBS, and with reduction or elimination of dopamine agonist therapy ICDs such as pathological gambling and others can improve [26–29]. However, several studies have noted de novo ICDs after DBS [30–32]. Interestingly, models of STN function [33] suggest that the STN modulates decision thresholds in proportion to reinforcement and decision conflict. Patients with STN DBS showed typical conflict-induced slowing in “win-win” computerized decision-making tasks with their DBS off, but 10 minutes after turning the DBS on, they exhibited less slowing and increased impulsive decision making in these same tasks [34]. Dopamine dysregulation syndrome (DDS) is a compulsive overuse of dopaminergic therapy. Preexisting DDS may or may not improve after STN DBS. Lim et al. found DDS remained unimproved or worsened in 12/17 patients after DBS, although this was a mix of STN and globus pallidus interna (GPi) DBS cases [32]. In the remaining 5/17 patients, DDS improved or resolved.Discontinuation of the DA or significant adjustment in dosage is the mainstay of treatment intervention and appears to be required to achieve full remission or significant reduction in behaviors [35]. Even still, some patients exhibit persistent pathological behaviors. A study examining psychosocial outcomes in patents having exhibited pathological gambling found persistent financial and marital stress as a consequence of these behaviorsalthoughfull or partial resolution of the behaviors in all subjects followed [36].Some authors group DA-associated behavior changes as disorders of impulse control, but careful examination of the behavioral issues reported in the medical literature and by our patients suggests a more complex behavioral derangement than a general disorder of impulse control. Patients appear to demonstrate a circumscribed obsessive-compulsion for a particular behavior. Most commonly, patients exhibit one particular obsession, but even in cases where two or more obsessions manifest, the more widespread injudicious decision making and excessive spontaneity that characterize a general disorder of impulse control are absent [20–23, 37,38]. It may be that the neural systems mediating these pathologic behaviors are more closely aligned with punding (an intense fascination with meaningless movements or activities such as collecting, arranging, or taking apart objects), and one study suggested a strong relationship between punding and the expression of dyskinesias. Some studies suggest a D3 receptor-dependent response to L-dopa and dyskinesia, at least in monkeys [13].Several recent studies have documented the importance of the brain circuits involved in reward and risky decision making, including, thalamic, striatal, and ventromedial frontal regions. Using fMRI, Reuter and colleagues compared pathological gamblers and control subjects and found that activation in regions such as the ventral striatum is inversely related to their pathological gambling severity, as if risks and rewards were less salient to pathological gamblers except at high enough magnitudes [39]. Another fMRI study had subjects play a game in which they decided to keep pumping up a virtual balloon or quit and collect reward points, with larger rewards associated with larger balloons [40]. Increased activation levels in insular, thalamic, striatal, and dorsolateral prefrontal regions bilaterally and medial prefrontal cortex/anterior cingulate regions correlated with increases in active risk taking. Functional imaging studies in PD patients have implicated similar brain regions [41, 42].Voon et al. [38] studied PD patients with and without impulse control disorders (ICD) in a risk task involving a certain (e.g., +$100) or an uncertain outcome (e.g., 50/50 chance of winning either $200 or winning $0) for both gains (+$) and loss (−$) domains. PD patients without impulse control disorders behaved more similarly to healthy controls while they were on DA medications, making substantially more risky choices when they were confronted with losses than with gains, thereby showing “loss aversion” [43]. These same patients made highly similar choices in the gain versus the loss domains without loss aversion when they were off DA medications. PD patients with ICD showed more risk taking in the gain domain whether on or off medication, a pattern that was opposite to those of the healthy controls and PD patients without ICD. Moreover, PD patients with ICD also showed higher sensitivity to risk when they were on DA medications, displaying a steeper drop in the number of risky choices as the value at stake became higher and higher. In another study [44], PD patients without ICD were given the Iowa Gambling Task (IGT) while they were on or off medications. In this task, subjects chose between four decks of cards with various risk reward payoffs (i.e., risk disadvantageous (RD) decks with larger and frequent rewards but also infrequent large losses leading to long-term net losses, versus risk advantageous (RA) decks with smaller frequent rewards but also smaller infrequent losses leading to long-term net gains). PD patients off DA medications showed an appropriate decrease in choices for the risk-disadvantageous (RD) decks over trials. In contrast, PD patients on DA medications failed to show such outcome-contingent learning; instead, they kept on choosing the RD decks.[h=4]4. Implications for Other Disorders[/h]Analogous behavioral changes arise spontaneously in the general population, where they are often termed “obsessive-compulsive disorder” or “addiction.” Obsessive-compulsive behaviors emerge in 30–50% of patients with Tourette syndrome [45], and recent PET imaging evidence suggests widespread dysregulation of extrastriatal dopamine response in subjects with Tourette syndrome relative to the response in control subjects [46]. As discussed above, this suggests a relationship between dysregulation of dopaminergic tone and obsessive-compulsive behavioral manifestations.The mainstays of pharmacologic treatment for obsessive-compulsive disorder are antidepressant medications whose primary pharmacologic target is thought to be serotonin (5HT), a strategy that meets with varying success. Consideration of the interaction between 5HT and dopamine in the limbic system provides another perspective on how these medications may be mediating that success. Rodent studies implicate D2 and D3 receptor activity in models of obsessive-compulsive behavior and found that D2/3 agonism ameliorated these behavioral models [47, 48]. The emergence of similar behavioral drug-induced compulsive behaviors in PD patients with no history of such behaviors and that the prevalence of these behaviors appears to show a dose-dependent response adds further credence to the relevance of dopaminergic stimulation in idiopathic obsessive-compulsive behaviors. In addition to inhibiting reuptake of 5HT and norepinephrine, clomipramine acts as an antagonist at the D2 and D3 receptors, which may explain in part the efficacy of clomipramine in treating obsessive-compulsive disorder. Taken together, these observations suggest that modulation of specific dopaminergic receptors may hold promise for new medications directed against obsessive-compulsive behaviors.Substance abuse literature suggests that liability to this disorder exists in 9–12% of humans. The D3 receptor does not appear to have a direct role in reinforcing the effects of drugs of abuse, but the role of the D3 receptor may be in processing novelty and in the environmental conditioning and associations that reinforce drugs of abuse, particularly those with psychostimulant effects. Initial studies in squirrel monkeys [49] and in rats [50] suggest an important role of the D3 and the closely related D2 receptor in mediating drug-related discriminatory behaviors, but they provide no evidence of a role of these receptors in direct reinforcement. The studies also suggest a role for these receptors in reinstatement of drug-use behaviors in abstinent animals. Taken together, these data suggest a potential role for D2/D3 specific ligands in decreasing relapse rates in abstinent drug abusers.[h=4]5. Conclusion[/h]In the brief time since DAs have been widely used for treatment of PD, an important association between higher doses of these medications and the emergence of pathologic behaviors has been recognized. As outlined above, the D3 specificity of these medications and over-representation of the D3 receptor [51, 52] likely account for both the lower incidence of dyskinesias and also for the emergence of these pathological behaviors. This observation has important consequences for the safe use and monitoring of PD patients taking DA-agonists. Although the anatomical underpinning of this neural connectivity is incompletely understood, this observation also suggests potential therapeutic targets for obsessive-compulsive disorder and possibly for substance-based addictions. Advances in understanding the roles of specific dopamine receptors may also help to guide drug design for future atypical neuroleptics that aim to reduce side effects while improving efficacy.

 

[MeDieViL]

I wasnt talking about selective D1 blockade, rather aps that also block this receptor, more selective aps dont block the anti anhedonic effect of simulants.

Let me also point out that in some individuals amphetamine wipe out ocd, like in my case, this refers to individuals that are in a way simular to people with shizophrenia, also in my case and others aps induce SEVERE ocd, this has been connected to childhood shizophrenia and indeed i suffered from bad negative symptions in childhood.

I think all those side effects arent actually a bad thing, they just go hand in hand, gambling can make you money, shopping gives us cool stuff, wild sex is the shit but unfortionally it goes without controll

Ive been looking into ways on how to gain back controll and its not that hard, as i want to patent that intervention i cant say much, but look at this research for example.

Just as hot bitches can blind you and make you act stupid, with a pharmaceutical intervention we can completely inhibit this, we can keep shopping to fun rather then being someone that has money but doesnt spend it, i dont know the neurobiology but the more money you have, the less you want to spend and keep it, i noticed it myself but you should go out.
Wild and dirty sex is good, just moderate it, and well gambling.. every addict won a shitload of money sometimes but they cant stop, but just as hot bitches make you act stupid this can be inhibited pharmacologically.

This is all based on a few of may hypothesisses im looking for subjects that can study some interventions but well, why do some ppl get rhich while others have no teeth? its all in the brain.

http://www.ncbi.nlm.nih.gov/pubmed/23595250
The honey trap effect, the gambling trap effect etc, its all simular
Ill try to find the reference where impairment of reward is associated with that pathological behavor, altough apvp and pdpv also cause me to be excessively sexual, and mdpv made my girlfriend gamble, im extremely ocd on this forum section and science, which is actually not that bad, i gained all of my knowledge while i was high on amphetamine, i cant focus or learn anything, however when manic i turn into a learning machine

 

[MeDieViL]

My finding are alot derivitive of some google books tough
anyway time for methylene blue to inhibit mania now, ill post more tomorrow

D2 and D3 are responsible for manic behavor, but methadone withdrawal made me really insecure man lol, this is a anoying experience, MB never fails as a anti manic tough hehe.

 

[theGirlWithBlueHair]

If they're not that selective, then chances are they are antagonizing the D2-like receptors, as well. If selective blockade doesn't block those effects, then it's unlikely that the inhibition of D1 activity is what's contributing to the eradication of the anti anhedonic effect; it would be the concomitant blockade of the D2/D3 receptors.

 

[MeDieViL]

Aps without d1 affinity only block the anti sa effects, olanzapine and risperidone leave me anhedonic on stims, amisulpiride, quetiapine, the one with the brand name buccastem dont.

 

[MeDieViL]

Im not saying selective d1 antagonists dont block the anti anhedonic effects, i havent got any.

 

[theGirlWithBlueHair]

Where have you heard of them blocking the D1 receptor as both of those medications you mentioned have negligible effects at the D1 site at clinically relevant dosages. Do you have a reference? And quetiapine isn't a potent antidopaminergic and doesn't bind tightly and stick to the receptors like the other ones do. Because of its unique activity at the D2 receptors, it allows for periods of normal dopaminergic neurotransmission. It's mostly an anti-serotonergic, -histaminergic, -adrenergic. Which is why it's considered somewhat recreational. And amisulpride is known for being selective for the autoreceptors at the lower dosage end, which increases synaptic availability of dopamine by overriding the cell's feedback mechanism. The two antipsychotics you mentioned are very unique compared to the others, whereas risperidone and olanzapine are high-affinity, full antagonists.

What dose of the compazine were you taking?, if you don't mind me asking

 

[MeDieViL]

Olanzapine and risperidone potently block D1 receptor at clinically relevant dosages, im talking about official doses, wikipedia dosages, i know about quetiapine i just wanted a example of a selective d2 one, i didnt count on someone clever haha. Oh shit risperidone doesnt block D1, but i do remeber reinstating the rewarding effect of amphetamine with the addition of nac, phenibut and curcumin, for whatever reason, either way i suppose their binding profile is too wide to conclude anything, except that on risperdal amphetamine was like placebo, while on olanzapine, stims made me feel normal while i still had anhedonia and social anxiety.

Im talking high doses of amisulpiride offcourse, antipsychotic doses, tought that would be obvious, also the autoreceptors would upregulate normalising dopainergic transmission after a couple days, its most likely anti anhedonic because of the GHB receptor. The other ap i talked about was chloproperazine which is extremely potent at D3, but yet again a ghb agonist which may mitigate any anhedonia blocking effect.

I suppose i should try haloperidol, and differened aps, altough im quite scared as they can induce a rapid unexpected shift in the brain causing severe long tern anhedonia, which doesnt seem to relate to any neurotoxic damage, rather some shift which ppl report after a few days or months, olanzapine ramdomly did it too me too, couldnt enjoy anything anymore long term, things where neurotral, not really unpleasant, i felt more normal then on olanzapine tough and better, which i would expect as all receptors should have been activated as normal.

NSI198 reversed this mostly untill i stupidly took olanzapine again, slowly awaiting the return of music enjoyment.

The internet is full of reports, high dose of magnesium and fish oil is reported to work over months but i dont have the time, read a succesfull anecdote of the combination of ropi and prami reversing ap induced anhedonia but the guy had to take the meds, so i need something to shock the brain into a shift of how i perceive things.

Kinda like how opiate withdrawal makes opiates work after a few days of withdrawal, because of some kind of shock i suppose, including dramatically changing the anti anhedonic effect i perceive of diff stuff. Also benzo withdrawal restores my sexual reward and blunted smell, another shock effect but its random and usually disappears when withdrawal lessens.

My symptions relate to shizophrenia which is caused by glutamate dysregulation, eg the brain acting dysregulated, ppl with shizo report diff effects of a med after they stop it and restart it, i do too, a med is never the same after i took a brake, this glutamate system regulates everything, and everything affects glutamate but its extremely unstable especially in shizophrenia.

 

[theGirlWithBlueHair]

You're right. Olanzapine does have a moderate affinity for the D1 receptor, but I would think that dosages >10-15mg would be needed to appreciably block this receptor given the dissociation constant.

Phenibut acts as a catalyst for dopaminergic activity in the brain because of its phenylethylamine structure, so that could be the reason why.

It's strange that risperidone antagonized amphetamine so much for you, as its dopaminergic activity is supposed to be relatively weak compared to it's activity at the 5-ht2a receptor site, where it is extremely potent. It's considered one of the prototypes of the "atypicals" because of this. Whereas olanzapine is extremely antidopaminergic at therapeutic dosages, but, then again, its extremely atagaonistic at all of its receptor sites, which is why its such a "dirty" drug.

I would recommend avoiding the butyrophenones like haloperidol as they can induce long-term changes in dopaminergic function, and have a very high proclivity for inducing movement disorders.

As for opioids working a few day after withdrawal, that would be due to the receptor upregulation that occurs. As for the benzo withdrawal, I would think that would be due to the increase in excitatory activity going on during the hypermetabolic syndrome that occurs during GABAergic withdrawals. I have blunted smell too, and withdrawals I've experience from baclofen and cannabinoids have caused the same thing, which slowly mitigates.

The d2/d3 agonists like ropinirole and pramipexole are very effective for anhedonia and amotivational symptoms, and are used off label for this quite often.

I hadn't considered amisulpiide's action at the GHB receptor when I wrote that post. Thanks for bringing that up. It's a good point. The GHB receptor is supposed to increase glutamate and dopamine receptors when activated so I assume it definitely plays a role.

I can understand what you mean about withdrawals "shocking" the brain... I've noticed this too. Especially from cannabinoids

Have you tried aripiprazole or cariprazine? the partial agonist antipsychs? Cariprazine is a new one and is supposed to be relatively selective for the D3 receptor and it's very interesting. You should look into it.

 

[JohnBoy2000]

0.088mg of pramipexole was scripted to me today.

That minimum dose, which I believe is comparable to 0.5 mg of cabergoline.

Like I mentioned, my doc is a flake, so - in terms of taking it, morning, midday, night etc - any pointers??

On 225mg of effexor now, which, after two weeks, isn't sufficiently impacting my symptoms.
Doc mentioned old school AD's - tricyclics, can be more efficacious.

Looking into that now.... will prob start a thread....

 

[theGirlWithBlueHair]

That pramipexole dose is pretty reasonable for starting out. Though I'm surprised he didn't at least give you .125mg. Did he only prescribe once a day, because usually it's taken bid.

As for when to take it. It depends on what you're taking it for. I would take it in the morning in order to get effects from it during the day. Taking it at night is usually to get beneficial effects towards RLS.

If the Effexor isn't working you could look into switching to the IR version (I'm assuming you're taking the XR based on the 225mg dosage). It's a lot more efficacious, and you can use higher dosages, upwards of 375mg, which would lead to more dopaminergic effects.

Have you tried bupropion at all?

 

[JohnBoy2000]

It mentioned on the pack that pramipexole can make one sleepy - induce fatigue, which is precisely what I'm trying to avoid.
Would that be considered a real issue with that med?

I'm taking it as a hopeful counter to the effexor induced sexual dysfunction, which is making me lose my damn mind if I'm being perfectly honest.

I haven't tried bupropion - it's marketed as zyban here, and comes only in 150mg xl version.

Today, I took effexor in the morning for the first time.
I think I had a little more energy than normal.
I'll continue it in the morning time for the next while, see what happens.


I was looking more so at the tri-cyclic group as a potential alternative, due to their potential direct effect on my symptoms.
Insomnia, appetite loss, low mood, IBS.

I understand tri-cyclics are actually more efficacious, but less well tolerated.
But in terms of weight gain and constipation - I actually NEED them things.

 

[theGirlWithBlueHair]

The real issue in terms of sleepiness with the dopamine agonists is that they can cause what are considered sudden "sleep attacks" where the patient can go from being wide awake and alert to nodding and asleep in an instant.

As for sleepiness in general, it is a common side effect, due to the inhibitory nature of the D2 receptors, but I wouldn't say "induced fatigue" - that's a term that makes me think of alpha antagonists/alpha 2 agonists and beta blockers, when you feel just burdened and weighed down by the drugs. Is that the type of feeling you are referring to?

It should counter the sexual dysfunction, which is very common with Effexor and something I experienced when taking it as well.

bupropion is a mild stimulant and is more effective than Effexor and doesn't cause sexual dysfunction and does cause appetite suppression in some people.

They are incredibly more effective, as for tolerance issues, it depends on the agent, as some of them can have a broad scope of action, amitriptyline for example, has effects on sodium, calcium, and potassium channels in addition to it's SNRI and anticholinergic effects.

 

[JohnBoy2000]

Wow - can tricyclics be taken in conjunction with mirtazipine?? - which has been a total life saver for me cause it helps me eat and sleep.

My former doc was greek, had poor english, and failed to grasp the gravity of my situation, so he straight up wouldn't script me tricyclics.
Fortunately, I've changed to a new doc that is more open to these things apparently.
Will be having first meeting with him next month.

In terms of fatigue I guess - by example, on lexapro, if I took it in the morning, I'd basically just be tired as hell all day long..
Now, without any meds, same deal - deathly tired.
But zispin helped with that, and effexor is seemingly assisting also.

Would effexor be considered a particularly "activating" anti-depressant??
I'm gauging in on contrast to the tri-cyclics, or even duloxotine.

 

[JohnBoy2000]

Given that, I'm guessing I'll try taking the pramipexole at night to start off with, and see how that goes.

In terms of it's half life or length of action, should the tiredness be gone by the morning time pretty much??