Bipolar disorder, mania, tricyclics and atypicals: the cases of clonidine and choline

[atara]

The hunt is on for mood stabilizers that don't have terrible side-effects. By 'hunt', I of course mean 'stumbling around in the darkness' and a small dose of 'trying to fix lithium'. Lithium is effective but it occasionally kills people who take it.

Antidepressants do not cause mania. Tricyclic receptor-profile drugs do. SSRIs do not. These are the binding profiles of the tricyclics:
http://en.wikipedia.org/wiki/Tricyclic_antidepressant#Binding_profiles

Compare to the atypicals:
http://en.wikipedia.org/wiki/Atypic...human_receptors_unless_otherwise_specified.29

These are antimanic. But they look like tricyclics on the binding profile. What gives? Well, the atypicals don't touch the transporters. SSRIs do, though. What's left? NET. Quick, let's look at some NRIs.

http://onlinelibrary.wiley.com/doi/...sCustomisedMessage=&userIsAuthenticated=false
SNRIs cause mania! What of the others?

Desipramine is a norepinephrine-selective antidepressant. It too causes mania:
http://psycnet.apa.org/psycinfo/1995-18585-001
Bupropion, however, does not. What can we make of this? Bupropion affects dopamine. Atomoxetine has caused some problems: http://journals.lww.com/psychopharm...Induction_Associated_With_Atomoxetine.24.aspx but not in conjunction with anticonvulsants: http://online.liebertpub.com/doi/abs/10.1089/cap.2005.15.996

We run into the problem that it isn't a popular study tactic to throw drugs at bipolar patients and try to make them crazy. Methylphenidate, for example, is fine in conjunction with mood stabilizers: http://onlinelibrary.wiley.com/doi/...sCustomisedMessage=&userIsAuthenticated=false but seems to be safe without them: http://online.liebertpub.com/doi/abs/10.1089/104454603322163844?journalCode=cap

So norepinephrinergic drugs obviously do something weird relating to bipolar. We don't know what, though.

Which brings us to clonidine. Clonidine is antiadrenergic via alpha-2. It is used as an abortive treatment for panic attacks. It also treats acute mania:

http://psycnet.apa.org/psycinfo/1987-11183-001
http://psycnet.apa.org/psycinfo/1987-11174-001 -- it is not as effective as lithium
http://www.ncbi.nlm.nih.gov/pubmed/2693073 -- measured, but not statistically significant against placebo
http://ajp.psychiatryonline.org/article.aspx?articleID=158561

Unfortunately clonidine only works about half of the time, this seems to be the rule rather than the exception.

The thing is, all of this time we've been assuming there's a "condition" called "bipolar disorder", a patient has the condition, and a drug treats the condition. But that isn't true. A patient has a condition, which has certain characteristics we call "bipolar". Everyone can only have one condition. The mixed results with clonidine were discarded, clonidine isn't considered as a possible anti-bipolar agent anymore, but seem to suggest: bipolar disorder may be segregated into clonidine-sensitive and clonidine-insensitive conditions. Look at the first study more closely:

"Ss who had had a good response to neuroleptics during a previous manic episode tended not to respond to clonidine."

Here "neuroleptics" usually means "dopamine antagonists". Bipolar patients who respond to clonidine respond less to dopamine antagonists; bipolar patients who respond to dopamine antagonists respond less to clonidine. We have a working theory. Atypicals antagonize both dopamine and adrenergic receptors, which seems sort of warm and fuzzy. The point of all of this, of course, is that clonidine is much milder -- way milder -- than most normal drugs given to bipolar patients, valproate, lamotrigine, quetiapine, etc.

So, is it possible that clonidine-sensitive bipolar disorder is a thing? Or were the clonidine successes just dumb luck?

Of course, the -other- difference between atypicals and tricyclics is mAChR. Here we have a much clearer picture: choline supplements do a thing, verified by multiple double-blind placebo-controlled trials.

http://www.ncbi.nlm.nih.gov/pubmed/7051871
http://www.sciencedirect.com/science/article/pii/0006322395004238
http://journals.lww.com/psychopharm...ndomized,_Placebo_Controlled_Trial_of.15.aspx

However, neither choline supplements nor bipolar-treatment drugs exhibit cholinergic activity in the brain! See:

http://www.biomedcentral.com/1475-2832/3/13
http://onlinelibrary.wiley.com/doi/10.1002/mrm.1910390619/full

Of course, we as humans have a thing called "intuition" and intuition would like to believe that more dietary choline --> more neural choline. The effects of choline given orally clash hard with our intuition. It doesn't work how we expect it to. But it does work. Three times, three double-blind studies, choline does something. But what the hell does it do?

END NOTE: bluelight ADD is a pharmacology discussion forum, but it is not a medical advice board. Please do not make treatment decisions for yourself, always consult a physician.

 

[MyExcuse]

Diagnosed Bipolar II and have been through the wringer related to medicine and my own experimentation. Everything you say sounds spot on with my experiences. Some commentary:

Cymbalta (SNRI) gave me incredible manic episodes and suicidal ideation, while Prozac (SSRI) did nothing negative except kill my sex drive.I personally responded well to both Seroquel and Clonidine and found both equally useful for mania. I personally did not stay with either for a variety of side-effects which I encountered. Neither was particularly good for depression.

I found myself most stable when I was simply taking L-Methyl-Glycine and Alpha-GPC. While the combo did not eliminate my mood swings entirely, it did lessen both manic and depressive states. I was the most stable I have ever been. I've since been prescribed Lamotrigine which works exceptionally well for my depressive states. I'm poor so I can't afford the supplement combo nor further experimentation.

There are a number of supplemental substances, such as choline, glycine, folate and others, which have not been explored nearly enough. It's a shame because most sufferers I've spoken with have a reasonable fear of the available treatment options, and so go untreated. I've yet to meet a doctor who knew or was willing to discuss supplements as add-on's to, or as independent treatments for bipolar disorder. Perhaps I've just had poor luck.

I applaud your research.

 

[ebola?]

I thought that SSRIs were known to occasionally induce mania in patients with bipolar. Is this only anecdotal?

The thing is, all of this time we've been assuming there's a "condition" called "bipolar disorder", a patient has the condition, and a drug treats the condition. But that isn't true. A patient has a condition, which has certain characteristics we call "bipolar". Everyone can only have one condition.

Ah. I think discussion of the ontology and epistemology (and ultimately, sociology) of psychopathology deserves its own thread. There were a few in PandS, one of them having some decent discussion therein.

ebola

 

[Hammilton]

I definitely and very quickly turn manic from setraline. Venlafaxine turned me manic within two w weeks.

 

[doctordog]

I haven't formally been diagnosed with Bipolar, but anything too noradrenergic (in laymen's terms) quickly destabilizes me. clonidine, on the other hand, was a miracle for anxiety (benzodiazepines induce a paradoxical reaction), but was far too erratic to make much therapeutic use of -- I've read it simultaneously agonizes and antagonizes NE receptors, and, once I grew tolerant to the anxiolytic effect, it just seemed to stimulate me. I'm trying to find a more selective NE-reducer .. guanfacine sounds good, but isn't available here; I'm interested in Prazoin, but am wary of the fact that it can be depressogenic.