Dive deep into the psychopharmacology of depression with Dr Patrick Finley, PharmD at UCSF. Learn practical tips including how to switch from one antidepressant to another, what to expect with SSRI and SNRI withdrawal, and how to choose a second (or third) antidepressant for refractory depression. We also summarize the safety around antidepressants in the peripartum period. ACP members can visit https://acponline.org/curbsiders to claim free CME-MOC credit for this episode and show notes (goes live 0900 EST).
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Written and produced by: Molly Heublein, MD
CME questions by: Molly Heublein, MD
Hosts: Matthew Watto MD, Paul Williams MD, Stuart Brigham MD, Molly Heublein, MD
Edited by: Matthew Watto MD
Guest Presenter: Patrick Finley, PharmD BCPP
Most patients do well with starting one of our best tolerated SSRIs, such as sertraline, citalopram, or escitalopram
When a patient’s depression does not remit with the first choice antidepressant, perform a quick taper and switch to a second choice option, for most patients another SSRI.
SSRI/SNRI withdrawal can cause common symptoms of dizziness, electric sensory phenomena, or flu like symptoms
Treating depression with SSRIs through the peripartum period is safe, and untreated depression is likely worse for perinatal outcomes.
It’s helpful to trend objective measurements to assess response to therapy:
Aim of depression treatment is remission aka a PHQ-9 score under 5. It’s not always possible. But it’s the goal. So, don’t just accept improvement in symptoms. Shoot for remission.
Dr Finley suggests considering the patient’s main symptoms of depression and targeting them.
Symptoms of cognitive slowing, sleeping all the time, eating too much- may respond best to norepinephrine/dopamine targeting medications.
On the other end of the spectrum, anxious depression may respond best to serotonergic or more sedating antidepressants.
SSRIs range from more activating (fluoxetine) to middle of the road (escitalopram, citalopram or sertraline) to paroxetine (more sedating). Paroxetine has other negative effects- strong CYP2D6 inhibitor, higher side effect profile, and worse withdrawal (Marken 2000 -PMID15014630).
SSRIs are generally very well tolerated, and have a lower discontinuation rate than SNRIs (Cipriani Lancet 2018).
When a patient does not have an adequate response to first line choice of SSRI, another SSRI is often the best choice (STAR-D -PMID18935932).
Sexual side effects are common with SSRIs. RCTs have shown augmentation with bupropion and sildenafil can be quite beneficial for both men and women in improving sexual function associated with SSRIs (Taylor 2005 -PMID16162361).
Dr Finley prefers to wean down the first line antidepressant quickly over 1-2 weeks. Then he swaps one low dose medication for another medication (also at a low dose). For example, if they’ve been on 150 mg sertraline, decrease to 100 mg for 1 week, 50 mg for 1 week, then stop sertraline. On the next day start 5-10 mg escitalopram as monotherapy. Go slowly if the patient is not tolerating a medication well. Everyone responds differently. Treatment must be individualized.
Other options include swapping directly from one moderate-high dose SSRI to another SSRI of similar strength over 1 day. This has been described in the literature as “tolerable”, but may carry a higher risk of side effects.
Transitioning from a high dose SNRI is a little more difficult due to higher rates of withdrawal symptoms. Dr Finley will occasionally lower venlafaxine to 37.5mg, for example, and then add a low dose SSRI to take concurrently for a few days- 1 week before stopping the SNRI (Keks 2016 -PMID27346915; Ogle 2013 -PMID23459282).
Withdrawal can commonly cause flu-like symptoms, increased anxiety, dizziness, “electrical phenomenon”- brain zaps, facial numbness, and lateral gaze visual stars.
Typical onset is 2-3 days after stopping a medicine, but some drugs with shorter half lives can have earlier onset (Keks 2016 -PMID27346915).
Paroxetine and SNRIs tends to cause more difficult withdrawal. Fluoxetine can be used to “self taper” if a patient is having a lot of trouble. That’s because its active metabolite has a half life around one week (Hirsch UpToDate 2018).
Dr Finley recommends using a treatment algorithm. Start with an SSRI. Optimize the dose. Swap SSRIs if needed. Determine if patient has remission or a partial response. Reassess residual symptoms and try to target those. Augmentation is often needed. In those cases, try adding a medication with a different mechanism of action. This can be synergistic. There are many options for augmentation. Choose an agent based on the type of depression:
Mostly for anxiety, pushing dose can cause dizziness/hard to tolerate. STAR-D trial showed a higher side effect profile. Rarely people have a paradoxical increase in anxiety.
These agents can be efficacious for anxiety and have the same effect on GABA. Dr Finley notes that pregabalin avoids the unpredictable absorption issues of gabapentin. Nevertheless, he starts with gabapentin as it is less expensive (Berlin 2015 -PMID26835178).
Mirtazapine is usually given as monotherapy. It’s good for those who are not sleeping, or someone who needs an appetite stimulant. It’s mechanism of action is different from other antidepressants. Dr Finley notes, it was originally designed as an antihistamine. Therefore, mirtazapine is very sedating at low doses. BUT, at higher doses the norepinephrine blocking effects become prominent. Consequently, higher doses have less appetite stimulation and sedation. Mirtazapine also blocks 5HT3 receptors (like ondansetron)– Croom 2009 -PMID19453203.
Hydroxyzine has some evidence for anxiety. Note: It is very sedating (Guaiana 2010 -PMID21154375).
L-Methyl Folate add on may benefit some patients- see more Folate section below (Fava 2009 -PMID19909688)
Atypical antipsychotics may be used as monotherapy or augmentation in depression. The biggest risk is metabolic syndrome. Dr Finley points out that aripiprazole and lurasidone have slightly lower weight gain risks. All atypical antipsychotics require periodic weight, cholesterol, and diabetes screening after starting treatment.
Vortioxetine may be used as monotherapy. Its has a unique mechanism of action blocking 5HT3, plus, multiple different agonist and antagonist effects at different serotonin receptors. This may be especially helpful in those with cognitive slowing due to depression. (Hirsch UpToDate 2018)
Bupropion as add on therapy may improve cognition, curb appetite, and improve energy. In Dr Finley’s experience, some patients feel too jittery and do not tolerate bupropion. It was more effective than buspirone in the STAR-D trial.
Multiple studies suggest that T3 has efficacy for add on to a variety of antidepressants. It may be more effective in women than men. It has rapid onset (Touma 2017 -PMC5451035).
Continue antidepressants for at least six months after achieving remission. Continue longer in patients with ongoing stressors, or a prior history of recurrent depression. Psychotherapy may help people do well off medication.
Dr Finley notes the risk of relapse is highest around two months after stopping antidepressants.
Iron may play important roles in healthy brain functioning and mental health. Low iron states may affect neurotransmitters levels (Kim 2014 -PMC4253901). An interesting small study showed that early iron supplementation significantly reduced postpartum depression in short term follow up (Sheikh 2017 -PMID26715522) .
Some research suggests that patients with MTHFR mutations may have reduced folic acid availability in the brain. Consequently, these patients have reduced neurotransmitter synthesis since folate is a cofactor in neurotransmitter production (ie synthesis of norepinephrine, serotonin, and dopamine). In patients with treatment resistant depression, Dr Finley suggests we check MTHFR gene status. Start L-methylfolate at 7.5 to 15 mg per day if low MTHFR activity. The idea is that L-methylfolate is able to cross the blood brain barrier while regular folic acid cannot. Some studies of augmentation with L-methylfolate in this population have been encouraging (Fava 2009 -PMID19909688, Owen 2013 -PMID24524097).
The risk of untreated depression is worse for baby’s health (Institute of Medicine Report 2009). Generally, it is safe to use SSRIs in pregnancy (with the possible exception of paroxetine). Sertraline is usually the first choice, but many others can be safely used.
An AHRQ report from 2014 noted the risk of adverse outcomes of antidepressants was very low. Abstinence syndrome may occur. The baby may have fussiness, and low appetite for 24 to 48 hours after delivery. In the worst case scenario, the baby may have short lived and self limited respiratory difficulties. Dr Finley notes that women on antidepressants tend to deliver earlier and their children often have lower birth weights. Nevertheless, the risk of untreated depression takes precedent and treatment should be continued if necessary.
Risks include: Unwanted pregnancy, not being in a healthy relationship, history of trauma, history of prior mental health disorders. Also, in a small study two candidate genes were very strongly associated. These genes of interest have serotonin receptor and estrogen receptor effects. Research is still preliminary in this area, but may help us understand who is at risk (El-Ibiary 2013 -PMID24307977).
No risk is associated with breastfeeding and antidepressants (SSRIs). Most SSRIs do get into breast milk, but only at low levels and do not seem to cause adverse effects.
Mass General Women’s Mental Health website has info for the general population and for providers.
Dr Finley suggests Stahl’s Essential Psychopharmacology: Neuroscientific Basis and Practical Applications by Stephen M. Stahl.
Don’t forget about psychotherapy. Medications can help acutely manage symptoms, and psychotherapy can help in the long term maintenance. Mindfulness can be a nice option too. Dr Finley suggests his patients try Headspace for guided meditation, or books by Jon Kabat Zinn eg The Mindful Way Through Depression; Wherever You Go, There You Are.
Don’t start antidepressant doses too high. A low dose like 5 mg of fluoxetine may be sufficient. No need to start sertraline at 50 mg daily- start at 25 mg or less. First ask, “does the patient tolerate a dose?”. Next, ask “are they benefiting?”. They won’t get to benefit unless they are tolerating the medication first.
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Listeners will adjust antidepressant therapy for the patient who is not responding to an initial agent, and feel comfortable managing peripartum depression.
After listening to this episode listeners will…
Dr Finley reports no relevant financial disclosures. The Curbsiders were sponsored by ACP’s MKSAP 18 for this episode.
Finley, Patrick. Guest, expert. “#140 Psychopharmacology 2.0”. The Curbsiders Internal Medicine Podcast http://thecurbsiders.com. February 18, 2019.
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