54 replies to this topic

[medievil]

http://zaldlab.psy.v...ns/mtt10nbr.pdf

Clearly explains how da has nothing to do with reward but that it does play a huge role in depression; this paper also supports my stand on the use of stimulants for depression or other issues with anhedonia; the tea with biscuits treatments dont cut it for that.

[Mr Black]

Interesting article. Thanks for posting it.

[nupi]

Great find, thanks for sharing. The point on page 9 about overestimating costs and underestimating benefits (at least to what others perceive them as, though I cannot shake the suspicion that the average person is biased towards underestimating costs) is spot on for me.


Now I only need to find an open minded neurologist to try dopaminergics and/or selective MAOI....

Edited by nupi, 03 June 2012 - 02:59 PM.

[noos]

What kind of stimulants medievil?

[medievil]

What kind of stimulants medievil?

Stimulants like amphetamine or its deretives, methylphenidate, 3FMA, MPA, ethylphenidate, camfetamine or perhaps craze or other stuff that acts as TAAR1 agonists wich some of the ingredients in craze do.

Treshold non psychedelic doses of psychedelics also work very well for anhedonia and have no tolerance issues at those doses.

In that paper wellbutrin was mentioned but that doesnt work for anhedonia it also barely raises dopamine in humans.

[medievil]

Amisulpiride because of its affinity for the GHB receptor also works for anhedonia but tolerance may be a issue.

I also found phenibut effective for anhedonia but tolerance may be an issue; even incredible fast for many, physical addiction occurs rapidly too but its easy as fuck to withdrawal with some diazepam for a week you wont feel a thing.

Perhaps ultra low doses of naltrexone could work because of mu upregulation and release of endorphines; those doses are far lower then the "low dose naltrexone" thing as in those doses it does actively block the mu receptor a bit.

Perhaps the same thing with ultra low doses of rimonabant wich upregulate the cannabinoid receptor.

[medievil]

Oxiracetam may potentially metabolise into gabob witch is a GHB receptor agonist and also ppl say it causes music enhancement wich can be related to that.

[Raza]

Great article, and I enjoyed your insights on resolving it too.

Now I only need to find an open minded neurologist to try dopaminergics and/or selective MAOI....

Ginkgo is a MAO-b inhibitor, and freely available.

Edited by Raza, 15 June 2012 - 08:36 AM.

[medievil]

I doubt MAOI's would help anhedonia.

[noos]

Thanks medievil. Will you include modafinil?

[noos]

" Treshold non psychedelic doses
of psychedelics also work very
well for anhedonia and have no
tolerance issues at those doses."

Once I read someone used very low dose lsd as nootropic

[medievil]

Yes they do indeed have nootropic effects the only issue is cardiac fibrosis with long term use.

[medievil]

I want to compile a ton of anecdotes to get a discussion started; if you just mention them there's a bunch of drugs are bad boys showing up only without interesting discussion.

[nupi]

I doubt MAOI's would help anhedonia.

If anhedonia is primarily a dopaminergic phenomenon then MAOI should very well help in my view. what else would you consider instead?

[medievil]

The paper says its actually not a dopaminergic problem but related to mu.

[nupi]

That is not really how I read it. It claims it is hard to pin down the exact role of DA but definitely implicates that DA regulation plays a major role. In any case, if people already think DA agonists are a dangerous game to play, then targeting mu seems positively out of question... But yeah, morphine would surely give more than complete relief from anhedonia - until receptor downregulaton sets in and you are in deep trouble...

[searchfunction]

The paper says its actually not a dopaminergic problem but related to mu.

That is not really how I read it. ...

If the paper states anything, it is that we must be more clear in communication. Anhedonia means different things for different people. In respect to the article, I suggest we be explicit in what we're referring to, lest the message of this paper be ignored.

"Specifically, we suggest that current clinical definitions of anhedonia are too broad. As the processes of reward wanting and liking are found to rely on separate neural systems, depression research must attend to these distinctions in order to develop specific neurobiological models and novel treatment targets. As a multi-faceted construct, anhedonia requires a more thorough characterization than is currently provided in the DSM or common selfr-eport assessments. We propose that clinical symptoms of anhedonia be divided into motivational and consummatory anhedonia in order to closely parallel the animal literature on reward."

... MAOI ...

... modafinil ...

From personal experience:
MAObI Selegiline provides increased motivation/desire.
Modafinil provides slightly increased desire and enjoyment of the present, quickly tolerant.
"10am feeling slight euphoria. motivated. i don't have any specific desires, but i still feel like i have a drive to get something. not a need like i'm missing something in life, but a want. it's like an excitement for nothing in particular. like YEAH THIS IS AWESOME I SHOULD KEEP DOING IT, but i'm not doing anything. euphoria total time: ~30mins. feeling passed towards more of a peaceful feeling."

[searchfunction]

Too late to edit post. I should've deleted "and enjoyment of the present", too vague.

... anecdotes to get a discussion started ...

Dopamine: Liking / Consummatory anhedonia?

[OP paper]
Finally, studies have found that increasing DA shows no effect on liking behavior. Genetically modified mice that exhibit a knock-down of the Dopamine Transporter (DAT) gene, thereby resulting in increased extracellular DA, showed no alterations in liking responses (Pecina et al., 1997). In sum, these findings provide clear evidence that DA function is neither necessary nor sufficient for hedonic liking responses to occur

→ source (external link)

Dopamine: Wanting / Motivational anhedonia?

[OP paper]
A second line of work has sought to demonstrate a pivotal role for DA in the motivation to pursue rewards, as indexed by over-coming response costs (Salamone et al., 2007). As shown in Fig. 3, Salamone and colleagues developed experimental paradigms that evaluate an animal’s willingness to work for a given reward ... rats enter a T-shaped maze and made a choice between one arm of the maze containing a readily available food reward (Low-Cost/Low Reward, “LC/LR”), and another arm containing a larger food reward that was available only after climbing a barrier (High-Cost/High-Reward, “HC/HR”). Using this choice-paradigm, it was demonstrated that while control rats prefer the HC/HR option, rats with NAcc DA lesions or blockade of striatal D2 receptors show increased preference for the LC/LR option.

→ source (external link)

Therefore, it is possible that psychostimulant-enhanced DA transmission in the BLA results in potentiated emotional salience and seeking (Ledford et al., 2003) of sexual reward, thus contributing to the enhanced sexual drive and desire reported by Meth abusers (Semple et al., 2002, Green and Halkitis, 2006).
...
mesolimbic DA efflux has been correlated to facilitation of the initiation and maintenance of rat sexual behavior (Pfaus and Everitt, 1995). Furthermore, DA manipulation studies show DA antagonists in the NAc inhibit sexual behavior, while agonists facilitate the initiation of sexual behavior (Everitt et al., 1989, Pfaus and Phillips, 1989). Thus, Meth may affect motivation for sexual behavior via activation of DA receptors.

→ source (external link)

Risk vs Reward Behavior / Decisional anhedonia:

[OP paper definition]
Using the preclinical literature’s focus on decision-making as a guide, it may prove useful to explicitly characterize anhedonia in terms of abnormal reward-based decision-making. Consequently, we propose that one manifestation of anhedonic symptoms may result in an impaired ability for normative decision-making. We term this “decisional anhedonia”, wherein the ability to balance costs and benefits when selecting among multiple options is impaired. We emphasize that decisional anhedonia is independent from cognitive or reasoning ability; making poor choices about complex financial instruments does not imply decisional anhedonia. Rather, we suggest that decisional anhedonia occurs when reward-based decision-making has (1) changed from a pre-morbid state and, (2) results in choices that substantially differ from normative decisions about potential cost–benefit choices. Importantly, we are not suggesting that decisional anhedonia is necessarily orthogonal to motivational or consummatory anhedonia. Rather, we suggest that the general, steady-state aspects of either motivational or consummatory anhedonia (or both), may lead to distinct decision-making impairments such that individuals overestimate future costs, underestimate future benefits, or simply fail to integrate cost/benefit information in a consistent manner, leading to erratic choice behavior. The critical benefit of focusing on a decisional anhedonia is that it provides clear behavior hypotheses and can be more readily linked to animal models. One key component of decisional anhedonia may be an overestimation of costs associated with gaining different types of rewards.

→ source (external link)

Recent data from our laboratory demonstrated that mPFC lesions result in continued seeking of sexual behavior when this was associated with an aversive stimulus (Davis et al., 2003). Even though this study did not investigate the ACA, it supports the hypothesis that the mPFC (and the ACA specifically) mediates the effects of Meth on a loss of inhibitory control over sexual behavior as reported by Meth abusers (Salo et al., 2007).

→ source (external link)

Of note regarding stimulants:

The current study demonstrates at a cellular level an overlap between neural activation by the natural reinforcer sexual behavior and the psychostimulant Meth. Therefore, these data show that not only do drugs act on the same brain regions that regulate natural reward, but in fact, drugs activate the same cells involved in the regulation of natural reward.
...
Moreover, these findings illustrate that in contrast to the current belief that drugs of abuse do not activate the same cells in the mesolimbic system as natural reward, Meth, and to a lesser extent Amph, activate the same cells as sexual behavior. In turn, these co-activated neural populations may influence seeking of natural reward following drug exposure.

→ source (external link)

[nupi]

One key component of decisional anhedonia may be an overestimation of costs associated with gaining different types of rewards.

I have a suspicion that addressing this would go a very long way. CBT studies consistently show that once depressed people actually go and do something even slightly pleasurable (even if they thought it would be not enjoyable at all, ex ante), they feel better than when just sitting around. And in any case, it would seem that you would have to address decisional/motivational anhedonia first, because even if consumatory anhedonia was resolved, if you lacked motivation to seek the pleasure that would not help at all. Conversely, if you only addressed motivational anhedonia, at least the patient would be able to live a productive life and get shit done - with or withou tenjoying the pleasurable parts of it.

The way I read the paper, DA agonists should help in addressing decisional/motivational anhedonia. Selegiline seems like a particularly interesting contender considering it is
1) A selective MAO-B (hence very small risk of Tyramine induced hypertensive crisis) which would boost primarily DA while leaving 5-HT and NE mostly alone (so less nasty side effects)
2) Neuroprotective
3) metabolized into l-amph and l-methamph (the largely non-toxic Amph and Meth-Amph enantiomers) which as shown by search function above might have an impact on their own

Which brings me back to the question of how one convinces a shrink or GP to prescribe a "nasty" MAOI (the idea that MAOI are not all made equal and indeed some of them are perfectly safe seems pretty foreign to them) that is mainly used for Parkinson patients...

Edited by nupi, 16 June 2012 - 11:48 AM.

[Raza]

I've never considered the L-amphetamine and L-Methamphetamine metabolism a plus. Mostly it'll get you insomnia and chronic nasal congestion, and it counteracts the benefit of a selective mao-b inhibitor not targetting norepinephrine.

I've had 100% L-amph - gawd knows why they made it like that - and it's downright unpleasant compared to mixed or pure Dex.

Edited by Raza, 16 June 2012 - 08:31 PM.

[nupi]

Well if you do not want the L-Amph, there is always Rasagiline that addresses those concerns. I guess in the end it would have to come down trying it for yourself....

[medievil]

Well, you can add craze to the list of effective treatments...

[protoject]

Well, you can add craze to the list of effective treatments...

I know this may be a bit off topic but I found amisulpride wholly uneffective for anhedonia, but I was wondering if you had ever combined amphetamine [like dexamphetamine] with low dose amisulpride and if this curtailed any d2/d3 agonising effects of amphetamine while enhancing its d1 effect, and if this is important...

[medievil]

In my experience above a certain dose it completely abolishes the anti anhedonic effect of amp indicating D2 and D3 play a crucial role in its anti anhedonic effect.
It makes sense as D1 and D4 are mostly related to the pfc and not the social, anti anhedonic etc effects.

Ami is cool stuff with its GHB agonism wich is the reason it works for anhedonia.

[medievil]

I havent read those papers suggesting anhedonia may be caused by expecting it wont be fun or overestimating the costs of it but didnt they conclude that by letting depressives or shizo's taste pleasant food and how much they liked it?

Doesnt mean much imo as the reward for food and sex is normal when i suffer from anhedonia, i also constantly do things that i dont get reward from wich rules out that i just think it would be boring.

[medievil]

Personally i had succes with:

Low daily treshold doses of AMT
Low daily treshold doses of 2CD
GBL
Amphetamine (or other designer stims)
Phenibut helps for 50% or something
Amisulpiride helped for a part too

They all have some issues, like GBL being addictive etc but due to the treatment resistance of anhedonia with the regular medications i beleive all substances should be mentioned with enough warnings about the risks.

Its not too difficould to treat when knowing what really works but many ppl stay in misery because those things have been excluded by mainstream psychiatry due to their addictive or other issues while efford to counteract those issues could have been done instead.

[medievil]

It appears that DHEA binds to the MU receptor, and indeed a study showing it helped anhedonia in a certain group of people after 6 weeks.

Also this thread is of high interest:
http://www.mindandmu...s-schizophrenia

This one is mostly of interest for those that have AVPD and relate a bit to shizophrenia.

Dhea has to be combined with real life effords and social exposure otherwise it wont help.

[medievil]

Also lets not forget that ne issues completely block the rewarding effects of most drugs in rodents, and indeed i saw some ppl mentioning nortriptelyne to resolve anhedonia.

Its a complex matter as its possible underlying issues block your ability to get reward, in those cases adding a rewarding substance wont help but the underlying issue has to be resolved.

[medievil]

With regards to GHB, it appears that the combo with a SSRI and naltrexone works well for alcohol addiction, the naltrexone should negate the reinforcing effects of GHB wich may turn GHB in a more therapeutical tool but thats up for debate.

Its a very addictive substance, but the italian study's indicate it may have some therapeutical potential. One thing is for sure, just blatantly taking will lead to a trainwreck.

Reconsidering GHB: orphan drug or new model antidepressant?

Bosch OG, Quednow BB, Seifritz E, Wetter TC.


Source

Clinic of Affective Disorders and General Psychiatry, University Hospital of Psychiatry, University of Zurich, Zurich, Switzerland. oliver.bosch@puk.zh.ch


Abstract

For six decades, the principal mode of action of antidepressant drugs is the inhibition of monoamine re-uptake from the synaptic cleft. Tricyclic antidepressants, selective serotonin re-uptake inhibitors (SSRIs) and the new generation of dual antidepressants all exert their antidepressant effects by this mechanism. In the early days of the monoaminergic era, other efforts have been made to ameliorate the symptoms of depression by pharmacological means. The gamma-aminobutyric acid (GABA) system was and possibly still is one of the main alternative drug targets. Gammahydroxybutyrate (GHB) was developed as an orally active GABA analogue. It was tested in animal models of depression and human studies. The effects on sleep, agitation, anhedonia and depression were promising. However, the rise of benzodiazepines and tricyclic antidepressants brought GHB out of the scope of possible treatment alternatives. GHB is a GABA(B) and GHB receptor agonist with a unique spectrum of behavioural, neuroendocrine and sleep effects, and improves daytime sleepiness in various disorders such as narcolepsy, Parkinson's disease and fibromyalgia. Although it was banned from the US market at the end of the 1990s because of its abuse and overdose potential, it later was approved for the treatment of narcolepsy. New research methods and an extended view on other neurotransmitter systems as possible treatment targets of antidepressant treatment brought GHB back to the scene. This article discusses the unique neurobiological effects of GHB, its misuse potential and possible role as a model substance for the development of novel pharmacological treatment strategies in depressive disorders.

Also please lets stay open minded in this thread, its obviously something that can end in a disaster but id like a open discussion about wheterthe downsides could be minimased.


With anhedo
nia being so hard to treat, i beleive we should look into other things, carefully discuss the dangers and then conclude what the possibility's can be.


I personally know G can ruin you, i definatly dont advocate it here but i stay with an open mind that it can help others (like how it appears to be used succesfully in italy and for narcolepsy.

Edited by medievil, 04 August 2012 - 11:41 AM.

[nupi]

This one is mostly of interest for those that have AVPD and relate a bit to shizophrenia.

Dhea has to be combined with real life effords and social exposure otherwise it wont help.

Who came up with the silly idea that AVPD is somehow related to schizophrenia? If anything, AVPD is a stronger version of SA, no? Or is the argument that AVPD is related to schioaffective disorder (which in turn seems to have relatively little in common with full blown schizophrenia, no?)