TCA's AKA the "dirty" SNRI's

The VA and Department of Defense have an extensive document about the treatment of Major Depressive Disorder (MDD). The first half of the document is about the appropriate diagnosis of MDD – I don’t think it’s important for clinical pharmacists to know all the details of this, since diagnosing is in the physician’s scope of practice. However, I do think it’s important for pharmacists to skim over this portion and at least be familiar with the symptoms to look out for. For example, if the mental health pharmacist (my preceptor) gets a consult on what to do with a pt’s antidepressant (d/t ADR’s, etc), then she will read the pt’s chart thoroughly. What if it turns out that the pt’s current symptoms don’t totally correspond to MDD, and just mild symptoms of depression? Does the pt really need the antidepressant? Can the dose significantly be lowered? Questions like these pop up, and it helps to at least be familiar with how various disease states are diagnosed. When I’m in practice, I really won’t be questioning diagnoses since that is not in my scope of practice unless I see something really wrong/dramatically affects my medication therapy recommendations. So…

1.       Diagnosis of MDD is made.

2.       Many 1^st line options.

a.       Selective Serotonin Reuptake Inhibitors (SSRI’s) – Paxil (paroxetine), Celexa (citalopram), Prozac (fluoxetine), and Zoloft (sertraline) – increase serotonin in synapse.

                                                               i.      Paroxetine: not for pregnant patients – category D related to CV malformations. Others are category C, but caution needed d/t pulmonary HTN in the baby. Plus, RISK of miscarriage, preterm labor.  Paroxetine also associated with increased D/C rates, increased weight, and increased sexual dysfunction.

                                                             ii.      Sertraline: increased diarrhea (mostly selective for 5HT3).

                                                            iii.      Fluoxetine: associated with decreased D/C rates. This one is also particularly activating – so consider in patients who are lethargic, etc. Has a LONG half life, and if need to D/C this drug, self-tapering is an option.

                                                           iv.      Citalopram: This was the “Step 1” therapy used in the Star*D trial (huge, pivotal study for treatment of non-psychosis depression). About 37% of study participants reached remission after just citalopram alone.

b.      Serotonin & Norepinephrine Reuptake Inhibitors (SNRI’s) – Cymbalta (duloxetine), Effexor (Venlafaxine) - increase serotonin and norepinephrine in synapse.

                                                               i.      Duloxetine: don’t use if pt has liver dysfunction or alcohol abuse. There’s no evidence of duloxetine being better than SSRI’s, but there is evidence for venlafaxine being about as efficacious as SSRI’s.

                                                             ii.      Venlafaxine: you don’t get a norepinephrine effect until at doses >200mg/day. So, until this dose, mostly going to be working on 5HT.

c.       Norepinephrine & Dopamine Reuptake Inhibitors (NDRI’s) – Wellbutrin (buproprion)  - increase norepinephrine and dopamine in synapse.

                                                               i.      Increased aggregion d/t the increased DA levels. This drug can be associated with weight loss, and not for pt’s with a history of an eating disorder like anorexia or bulimia. Also can decrease seizure threshold, so avoid in seizure pts. If pt is looking to quit smoking, this medication could be a “2 for 1” deal and help with depression and smoking cessation. Bupropion has also been well studied as an adjunct therapy if other antidepressants were working , but just short of remission.

d.      Remeron (Mirtazapine)

                                                               i.      Major mechanisms of action are H1 blocker and alpha2 antagonist. When I think of a H1 blocker now, I automatically think of sedation and weight gain. In fact, mirtazapine is one of the strongest H1 blockers out there – even stronger than our antihistamines (Benadryl, etc.). Which means it’s also associated with lots of sedation and weight gain. It also acts as an antagonist to alpha2. Remember clonidine? Alpha2 agonist, which tells alpha2 there’s enough NE in the body, and to signal to stop production. Decreased NE then causes less vasoconstriction, and leads to tx of HTN. Well mirtazapine is just the opposite – alpha2 antagonist >> more NE >> tx for depression. So, makes sense that one of the ADRs is HTN. Mirtazapine is a great example of how the maximum dose of an antidepressant should be tried (as long as pt can tolerate) before claiming a treatment failure. If a pt is on a 15mg dose, then most of the drug is hitting the H1 receptor…and pt will feel sedated most of the time – great for sleep if pt is also having trouble sleeping, but not excellent for the depression. However, at a higher dose, more drug is able to inhibit the alpha2 receptor, and increase NE production. This is an activating neurotransmitter, antidepressant properties can be more apparent now. Of course every pt is different though, and some may just require the 15mg dose.

3.       TCA’s AKA “dirty” SNRI’s. They are SNRI’s as well as anticholinergic, alpha1 blockers, and histamine blockers – amitriptyline, nortriptyline, imipramine, desipramine, doxepin

a.       Contraindications: post MI, hypersensitivity to the class of drugs, angle closure glaucoma, CVD (CHD with abnormal EKG), orthostatic hypotension, suicide, cognitive impairment (especially in elderly).

b.      ADRs: anticholinergic effects,  CV (OH, syncope, arrhythmia), CNS (sedation, confusion), weight gain (especially amitriptyline and doxepin), sexual dysfunction, decreased seizure threshold.

c.       If NEED to use a TCA in the elderly, notriptyline or desipramine first line. But only if you NEED to.

d.      Clomipramine is also a TCA, but only approved for OCD.

4.       Monoamine Oxidase Inhibitors – isocarboxazid, phenelzine, tranylcypromine, selegiline (transdermal).

a.       Last line.

b.      Pt needs to be well educated about avoiding tyramine-containing food (ex. cheese, wine, etc.), stimulants, and vasoconstrictors d/t risk of HTN crisis.

c.       Cannot take with antidepressants, triptans, meperidine, tramadol, propoxyphen, dextromethorphan d/t risk of 5HT syndrome.

The picture that shows up on Wikipedia's MDD page. Artist - Van Gogh. No, I didn't use Wikipedia to get any of the clinical information - just the picture ;)!

Other Drugs Facts

·         TCAS’s: question – would increasing the dose provide better treatment for sleep? No, since a low dose should be hitting and saturating the H-receptors.

·         SSRI – should be taken in the AM because it can cause insomnia (^5HT in the body).

·         Amitriptyline most associated with anticholinergic effects out of the TCA’s.

·         Imipramine mostly affects 5HT, not very anticholinergic and alpha blocking, but fairly high histamine block.

·         Doxepin – STRONG histamine blocker.

·         As you increase the dose of the above 3 meds, starts becoming less selective for the receptor it acts on the most.

·         SSRI and TCA combination – SSRIs increase TCA concentration about 3 to 4-fold d/t blocking CYP2D6. Fluoxetine is most notorious for blocking 2D6.