Jan, I do not have a direct, experienced based answer for you. However, I am betting that it is safe from a hyper metabolic syndrome risk perspective. The best experiential data might come from the neurology community that treats Parkinson's Disease. Experience combining direct DA agonists with deleting and COMT inhibitors might shed a bit of experience light on the matter, although still not quite the same.   Charles

Hi Jan. I do not have direct experience but I agree with Charles and would add that pramipexole is a D2/3/4 partial agonist and direct acting DA agonists would not be expected to produce the same pressor effects as, say, uptake inhibitors or stimulants (which you and I have used successfully with MAOIs). Please let us know if you do it and what happens.

Jan

I have used pramipexole at a dosage of .5 to 2 mg in patients also taking tranylcypromine, usually prescribed at 40 mg/day or lower.  No problems have ensued.  However, on a few occasions with pramipexole alone, but at higher doses; 3-4 mg, have seen various types of increased risky behavior.

Charlie

Jan, very interesting question. I used frequently pramipexole as add on to all antidepressants but still today not as add on to MAOI. The experience of Charles is usefull for me. Thanks

The risk of a hypertensive crisis is a real phenomenon only with ISA (Indirect Sympathomimetic Agonists) like ephedrine, pseudoephedrine, amphetamines derivatives (these lasts only in high doses, because at low doses these are safe augmentation drugs for MAOI). Then, there are not hypertensive risk with direct dopaminergic agonists like pramipexole or ropinirole.

In fact, in Parkinson disease treatment, the similar association between dopamine agonist and selective MAO B inhibitors are a common rule of therapy.

However, I have never combined MAOI like tranylcypromine - that I use - with direct dopaminergic agonists because I think there is a weak rational to do this and I think it can only worsen some aspects such as irritability, hypersexuality and gambling. Indeed, treatment resistant depression is not a Parkinson disease (unless it is a prodromal symptom of a nigro-striatal neurological degeneration, that it can be) and the dopamine increase guaranteed from only MAOI use, especially from tranylcypromine over phenelzine - for preferential binding to MAO-B - is normally overabundant.

Then, if with a MAOI a partial response occur, a better augmentation strategy, especially for residual apathy, lack of initiative or energy, is the combination with noradrenergic tricyclic antidepressants like amitriptyline - that can improve the sleep pattern, no rarely compromised with TCP - and its less sedative and more "stimulant" metabolite nortriptyline. Moreover, these last drugs, through the strong inhibition of tyramine reaction, can greatly reduce the risk of developing hypertensive crisis.

Greetings from Dr Nicola Mosti,

disciple and collaborator of Dr Giulio Perugi

Nice thread indeed.

I agree with above, Including with Dr. Shelton, who properly points out the differential profile of pramipexole vs. NDRIs or other drugs acting on the transporter, or those rather concurring to direct or indirect re-uptake inhibition. Dr. Bowden also points the chance of increased impulsive and aggressive behavior. Pramipexole is well known also for its ex-novo or de-novo induction of impulsive dyscontrol behaviors (especially in vulnerable subjects as the Parkinson's patients who may exhibit pathological gambling or delusional jealousy and aggressive behavior). So, yes, this is an also an issue to account for.

I think one other issue to consider here is that phenelzine and tranylcypromine are both irreversible and non-selective MAOIs. Yet, they differ against each other.

Phenezline is slightly more active on MAO-A, though being a strong inhibitor of both MAO-A & B. One of its metabolites significantly inhibits GABA-transaminase, which means that it may be slightly more effective for anxious depression (anyway anxiety is among the core features of atypical depression and would affect the outcome of pharmacological response, where for the good, where for the bad, as originally reported by West and Dally in 1959). Similarly, this should also mean a preferential activity against additional atypical cores of depression, including psycho-motor agitation. Also, phenezline is possibly the safest Irreversible MAOI to try augmentation with, basically because a number of anecdotal clinical reports suggested one could slightly exceed the approved maximum dose of 90mg (usually up to 120mg/day). This is a plus when considering augmentation with monoaminergic drugs, including the D3/D4 agonist pramipexole. Maybe ketamine too, but that would be a different story and indirect modulation, including NMDA activity. I have no experience about that so far, but I would be glad to read about that from any of the experts who already contributed to this thread.

On the other side, tranylcypromine slightly prefers MAO-B, but it is still a strong  inhibitor of MAO-A too. It is probably the most effective MAO for depressive disorders but, like selegiline, it may not be the best option when there is significant anxiety. Some prescribes may go beyond the usual 10-30mg in mono-therapy, up to 60 (or 90 for treatment-resistant cases). Thus, I would guess that an augmentation should be attempted with low doses, initially, and then slowly up-titrated.

In addition, I would reconsider the diagnosis too before attempting high risk augmentation strategies. Subtle bipolar features, namely atypical and/or mixed features should solicit accounting for lithium too. Obviously, I acknowledge all of the above senior experts would be aware of this and that notion that even lithium itself is not void of any risk when prescribed with a MAOI (still provides a weak pro-serotonergic activity too).

Finally, I would also like to point out the following:

MAO-A breaks down serotonin, NE, epinephrine (and melatonin too). Of course, I t also degrades tryamine. On the other side, MAO-B is the enzyme for DA, and it is more involved in phenethylamine. Obviously, the is no clear-cut split of activity of the two types of MAOs as they partially overlap, yet, tranylcypromine would possibly be slightly more pro-dopaminergic. This should be considered when attempting augmentation with pramipexole I guess. Yet, again, MAO-A inhibition is also associated to an increase in DA levels and prolonged exposure time in the synaptic cleft.

While inhibition of MAO-A is the only way to achieve antidepressant effects, inhibition of MAO-B exerts stimulation effects and may reduce the lag phase of anti-depressive repose, if ever, and increase energy overall. This belief is given credence by some clinicians by the fact that non-selective MAOIs outperform selective MAOIs as antidepressants.

Michele Fornaro, MD, PhD.