Your experience isn't unusual. There is now considerable evidence that ADs, especially the SSRIs, can become progressively less effective every time they are stopped and restarted, often requiring higher doses to achieve the previous level of control, or not working at all. They may also produce more severe, and/or different, initial side-effects. Two studies,
Amsterdam JD, 2016 and
Amsterdam JD, 2009, found the likelihood of antidepressants working after each restart drops by between 19-25% (see also:
Bosman RC, 2018;
Amsterdam JD, 2009;
Leykin Y, 2007;
Paholpak S, 2002).
Despite what is says on the tin, venlafaxine is only a SSRI, not a SNRI, and has few advantages over the others and several significant disadvantages.
The other issue may have been the diazepam. Benzodiazepines (BZDs) may significantly reduce the effectiveness of antidepressants by blocking hippocampal neurogenesis which is how ADs create the therapeutic response (see:
Boldrini M, 2014;
Nochi R, 2013; --
Sun Y, 2013;
Song J, 2012;
Wu X, 2009;
Stefovska VG, 2008).
In light of these studies benzodiazepines use should probably be limited to a couple of weeks when first taking antidepressants just to ease the initial increase in anxiety levels, for a while after AD dose increases for the same reason and thereafter for occasional breakthrough anxiety. If an antidepressant isn't adequately controlling anxiety on its own even at the maximum recommended or tolerated dose then switching to another which might be more effective should be considered ahead of supplementing it with a benzodiazepine.
Unfortunately, it is an all too often seen outcome once psychiatrists use up their personal small bag of tricks so resort to just throwing more and more drugs at the problem without rhyme, or reason in the usually vain hope that something will stick.
Vortioxetine (Brintellix, now Trintellix) is on paper a superior SSRI, but it hasn't set the world on fire. Mirtazapine is, as with venlafaxine, not what it claims on the tin. It is really only a sedative, not an antidepressant (and a powerful antihistamine). I don't understand the point of prescribing both pregabalin (Lyrica) and diazepam as they do the same thing, slowing neuron firing, albeit by different means. Diazepam does it by increasing the influx of negatively charged chlorine ions into cells which makes it harder for them to reach their depolarisation ('firing') voltage, pregabalin by inhibiting the ingress of positively charged calcium ions. There may be a rationale for preferring pregabalin over diazepam, but if you're also going to prescribe the BZD anyway then you might as well prescribe it at a high enough dose to do the job on its own as it is generally more effective than pregabalin.
I can't say whether imipramine will work for you, but the chances are pretty good. Imipramine was for many decades the 'gold standard' AD for panic disorder. Doctors now prefer to prescribe SSRIs and SNRIs because they are perceived to be safer in overdose, which isn't actually true of all of them, and to have fewer ongoing side-effects which is true, but often at the expense of more severe initial side-effects and harder withdrawals, not because they are more effective. TCAs are generally superior in performance, although, as with everything antidepressant, individual results may vary.
From what you've written vortioxetine isn't actually doing that much so will you really lose anything by quitting? I suspect it's mainly the mirtazapine, pregabalin and diazepam doing the heavy lifting. You could continue to take them while waiting for the imipramine to kick-in.
Did you had problems with tachycardia on venlafaxine? It is more cardio-toxic than the TCAs, except dosulepin. Imipramine was the first AD I took at doses of up to 350mg/day. Few doctors would prescribe that high a dose even for hospital inpatients, but my heart didn't care (still doesn't with the even more cardio toxic TCA (dosulepin) I'm now on despite being 30 years older).
Why not a MAOI? They are generally the most effective ADs often working when nothing else will. There used to be issues with diet which is why I stopped taking phenelzine (Nardil) back in the day despite it being the best AD I've tried, but modern food processing techniques have eliminated most of the problems and adding a small supplementary dose of the TCA nortriptyline will block any blood-pressure spikes if one of the few remaining tyramine rich foods is inadvertently eaten. Should dosulepin ever poop-out on me the first thing I'll be trying is tranylcypromine (Parnate).
Originally Posted by SideFX
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