u/NewEstablishment1327

I have chronic severe depression with extremely low energy and impaired functioning. My main problem is not anxiety itself, but inability to sustain work/study or even basic daily activity consistently.

Medication history:

Venlafaxine monotherapy (up to 300 mg) → hypersomnia (~15h/day), emotional flattening, loss of motivation

Amitriptyline (150 mg) → the only antidepressant that significantly restored functioning/productivity, but caused major side effects (orthostatic issues, cognitive impairment, heavy anticholinergic burden)

Fluoxetine → initially helped anxiety, obsessive/paranoid ideation, and social fear, but after ~2–3 months caused severe apathy and inability to function

I’ve also tried multiple SSRIs, milnacipran, several antipsychotics (including low-dose augmentation), mood stabilizers, etc., without meaningful benefit.

Current plan from psychiatrist:

venlafaxine (~225 mg)

mirtazapine (30–45 mg)

Main questions:

In patients who became apathetic/emotionally blunted on venlafaxine alone, does adding mirtazapine sometimes meaningfully improve motivation/functioning?

Does this response pattern sound serotonergic-related, or is that too simplistic?

Amitriptyline uniquely improved my ability to function despite heavy side effects — is there any pharmacological explanation for why a TCA would help functioning where SSRIs/SNRIs mostly produced apathy?

After amitriptyline, I developed persistent hypersensitivity to nicotine: even tiny amounts now cause tremor, numb/heavy feeling, cognitive dysfunction, and feeling physically “poisoned.” This has persisted for ~1 year. Is there any plausible cholinergic/nicotinic mechanism that could explain this?

Given my medication history and limitations, are there any other pharmacological strategies that might still be worth discussing with a psychiatrist?

Unfortunately stimulants, bupropion, and MAOIs are not realistically available where I live.

My primary goal is simply restoring enough functioning to work consistently again.

I’ve been stuck in a state where I basically have no drive or mental energy left and can barely handle normal life/work.

Venlafaxine by itself made me sleep a lot and feel emotionally flat. Fluoxetine helped anxiety and paranoid/obsessive thinking at first, but eventually I became too apathetic to keep functioning normally. Oddly enough, amitriptyline was the only antidepressant that actually made me productive and able to study/work, but the side effects became too hard to tolerate physically and cognitively.

I’ve already gone through multiple SSRIs, some antipsychotics, mood stabilizers, etc., without much improvement.

My psychiatrist now wants me to try venlafaxine together with mirtazapine.

For people who’ve tried this combo:

* did it help with actual functioning and motivation? * did it feel different from venlafaxine alone? * is there anything else worth considering for treatment-resistant low-energy depression if stimulants/MAOIs aren’t available?

At this point my biggest goal is simply being able to work consistently again.