I'm curious about other people's experiences and knowledge with NRI's.
The one's that I know of are Desipramine (Norpramin), Nortriptyline (Pamelor), atomoxetine (Strattera), and reboxetine (Edronax).
I have personal experience with Nortriptyline at 150mg a day which puts my blood levels on the lower end of the therapeutic window. I'm a fast metabolizer of this medicine so most people wouldn't take as much as me to get the same blood levels.
Nortriptyline has significant antihistamine effects, granted no where close to that of the older tricyclics like amitriptyline or imipramine. For me, this helps me fall asleep and the sedation has worn off by the time I'm ready to wake up.
In the day, it provides a very subtle and mild mental stimulation that helps me stay on task and focus and I can drive a car in rush hour traffic without blasting heavy metal and/or having coffee before hand. This is probably the NRI effect and also might have something to do with it's 5ht2a/c properties.
It does have some alpha1 activity which causes orthostatic hypotension which in turn can cause dizziness upon standing.
There is also it's muscarinic antagonism which for me in addition to the antihistamine effects eliminates my nervous stomach syndrome syptoms entirely. For others, it might cause brain fog, constipation, sedation, and weight gain. This mach antagonism very well might be a significant part of it's antidepressant effect given the much lower effectiveness for reboxetine and strattera.
It does help a ton for anxiety and gives me a lot of relief but not full relief (on it's own) from depression. It does cause an increased pulse for me but blood pressure is unaffected.
It has no more overdose potential than most SSRI's. The same is true of Desipramine. The same cannot be said of the older tricyclics.
I haven't taken Desipramine, but my understanding is that it's usually mildly to moderately activating and is more selective for NRI than nortriptyline which may or may not be a good thing depending on individual. Both of these are probably the most effective NRI's for depression and anxiety.
Desipramine used to be prescribed a lot more for adhd before the stimulants became popular.
Both Nortriptyline and Desipramine have poten 5ht2a/c antagonism effects which make them pair very well with SSRI's since that effect will mitigate some of the SSRI side effects. The stomach easing effect of nortriptyline gets rid of the stomach problems lexapro gives when I take them at the same time.
Arguably, both these tricyclics don't have any more sides or safety issues than the SSRIs.
I don't know much about Strattera or Edronax and have taken neither. I know Strattera was developed to be an antidepressant that had the NRI effects of tricyclics but without as many bad sides and it failed on both counts despite being much more selective. But it was effective for treating adhd so that's what it marketed for. This is one of the pieces of evidence that suggest the broad spectrum of effects in tricyclics might be part of it's therapeutic effect, not just the sides.
I know Edronax wasn't proven effective enough for depression to be marketed as such in the USA. When I read reports of it, it's usually used to augment other antidepressants or help with the sides of other antidepressants. I haven't found trials for adhd, but anecdotal reports suggest some success.