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SSRI/SNRI & Protocol UT Health Science Center at Tyler - October 2019 Michael Garner, PharmD Candidate, Class of 2020 Chimnonso Onuoha, PharmD Candidate, Class of 2020

O’Neill Niyomugabo, PharmD Candidate, Class of 2020

Assessing Patient Response The determination of treatment success or failure is based upon the change in PHQ-9 scores from baseline. ● 50% change from baseline indicates a partial response a. If the patient has a partial response to an -like an SSRI, and it is not at max dose, then we would titrate to the max and wait for 6 weeks ● > 50% change indicates an improvement in depressive symptoms ● < 50% change indicates treatment failure 1. Titrate up to max therapeutic dose 2. Add a to increase efficacy 3. Switch the medication. i. Switch to another SSRI; If the second SSRI does not work as well, switch antidepressant classes When interpreting patient response, an antidepressant trial of 4-6 weeks is required to see an initial response, 6-8 weeks is required to determine an adequate trial. Adolescence and young adults may require close follow up as there is an FDA black box warning on for increased risk of suicidal ideation and behavior in that age group. Precipitating factors that may affect patient response include older age, diagnosis, worse physical functioning, and lower energy level (Corey-Lisle, 20004). The persistence of adverse effects, such as gastrointestinal (GI) symptoms (eg, nausea, vomiting, and ), sexual dysfunction, , and insomnia may also affect patient response.

Add-On to Increasing Antidepressant Efficacy Lithium and can be prescribed with antidepressants to boost their efficacy. Lithium is not metabolized by CYP so it is exempt from CYP drug interactions, however, it can still precipitate serotonergic effects and may interact with SSRIs. Buspirone is metabolized by the CYP3A4 , which is inhibited by and .

Switching Antidepressants Complications that may occur from switch between antidepressant classes depend on the characteristics of the individual medications. Factors such as medication half-life, , and side effects must be considered when selecting a new medication. In some situations, there are therapeutic options to mitigate specific side effects that may be contributing to the patient’s poor response. ● (Low Risk): and are the least likely to interact with a new drug because they have a short half-life and have little effect on the CYP450 enzyme system. ● (Moderate Risk): Fluvoxamine and inhibit major P450 enzymes but linger in the body for only a week or so after discontinuation. ● (High RIsk): Fluoxetine potently inhibits P450 enzymes and has the longest half-life of the SSRIs. ○ TCAs, , and have the highest risk of interactions when switching. They are metabolized by CYP2D6 and cause cardiovascular toxicity, , and , respectively Antidepressants / Approximate Half Lives (days) SSRI SNRI ● Citalopram (Celexa) / 1.5 ● Desvenlafaxine (Pristiq, Khedezla) / 0.4 ○ Risk of QT prolongation ● (Cymbalta, Irenka) /0.5 ● (Lexapro) / 1.5 ● Venlafaxine (Effexor XR) / 0.6 ● Fluoxetine (Prozac) / 4-16 ○ Supported use in menopausal woman ○ Most activating ● Fluvoxamine / 0.6 ○ Most sedating ● Paroxetine (Paxil, Pexeva) / 1.0 ○ Possesses the most anticholinergic ○ Most sedating effects ● Sertraline (Zoloft) / 1.1-1.3

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Techniques for Switching: Conservative Switch: ● Most appropriate for general practice, 1. The first antidepressant is gradually reduced and stopped ● Low risk of drug-drug interactions 2. Drug-free washout interval of five half-lives of the first ● Discontinuation may occur antidepressant 3. The new antidepressant is started according to its dose recommendation

Moderate Switch: 1. The first antidepressant is gradually reduced and stopped 2. Drug-free washout interval of 2-4days 3. The new antidepressant is started at a low dose, and tapered to the therapeutic dose

Direct Switch: ● The risk of drug interactions is 1. The first antidepressant is stopped substantial, depending on the second 2. The second antidepressant is started the next dat at the antidepressant. Method requires clinical therapeutic dose expertise and is only feasible in selected instances, such as swapping from one short half-life SSRI to another.

Cross-Taper Switch: ● Frequently used for patients with high 1. The first antidepressant is gradually reduced and stopped risk from illness relapse but there is a 2. The second antidepressant is introduced at a low dose at risk of drug interactions and increased some stage during the reduction of the first antidepressant, adverse effects from combined so the patient is taking BOTH antidepressants medications. Only feasible in selected simultaneously instances. Requires clinical expertise. 3. The second antidepressant is increased to the therapeutic dose when the first antidepressant has been stopped ● [Australian prescriber, 2016]

Strategies to Mitigating Specific Side Effects: Insomnia The SSRIs and SNRIs can disrupt sleep patterns in some patients, they abbreviate the rapid-eye-movement (REM) stage. Strategies to reduce insomnia include; ● Taking the medication in the morning ● Switch to 15 mg or 30 mg ○ At higher doses (45 mg), the sleep-aiding effect may be reduced. ● Low doses of TCAs( , , and nortriptyline) ○ These agents may be used as an adjunct to another antidepressant to enhance sleep and mood. However, the TCAs also shorten the REM stage of sleep ● Add 25–150 mg ○ When used as an antidepressant doses of 300–400 mg the sedating effects can be limited ○ There is an increased risk of priapism in male patients Sexual Dysfunction SSRI, SNRI, TCA, and MAOIs have the highest rate of sexual dysfunction. Antidepressants with the lowest rate of sexual side effects include: ● Bupropion (Wellbutrin XL, Wellbutrin SR, Aplenzin, Forfivo XL) ● Mirtazapine (Remeron) ● (Viibryd) ● (Trintellix) Strategies to mitigate sexual dysfunction include: 1. Waiting a few weeks to see if symptoms improve 2. Adjusting the dose 3. Switching to another antidepressant 4. Adding a second antidepressant or another type of medication a. Bupropion b. Sildenafil (Viagra), tadalafil (Cialis) or vardenafil (Levitra, Staxyn)

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Switching between specific Antidepressants

From ↓ To → Citalopram Fluoxetine Fluvoxamine Desvenlafaxine Escitalopram Duloxetine Paroxetine Venlafaxine Sertraline

Citalopram Taper drug, start Taper and stop drug, Taper and stop drug, Taper drug, start Escitalopram alternative SSRI at low then start fluoxetine at then start fluoxetine alternative SSRI at Paroxetine dose 10 mg at 50 mg low dose Sertraline

Fluoxetine Stop fluoxetine (or taper Stop fluoxetine (or Taper and stop if dose >40 mg/day), taper if dose >40 fluoxetine, wait 7 wait 7 days for washout, mg/day), wait 14 days for washout, then start above SSRI days for washout, then start SNRI at at low dose then start low dose fluvoxamine at 50 mg

Fluvoxamine Taper and stop Taper and stop Taper and stop fluvoxamine, then start fluvoxamine, then start fluvoxamine, then above SSRI at low dose fluoxetine at 10 mg start SNRI at low dose

Desvenlafaxine Taper SNRI, start above Taper and stop SNRI, Taper and stop Taper SNRI, start Duloxetine SSRI at low dose* start fluoxetine at 10 SNRI, start alternative SNRI at Venlafaxine mg fluvoxamine at 50 low dose mg ● [Australian prescriber, 2016]

Tapering Antidepressants to Discontinue Interrupting or abruptly discontinuing antidepressants can lead to a number of complex physiological and neuropsychiatric syndrome commonly referred to as antidepressant discontinuation syndrome (ADS) [Warner, 2006;Fava,2015]. Symptoms of ADS can be easily identified using the acronym FINISH, Flu-like symptoms, Insomnia, Nauseous, Imbalance, Sensory disturbances, and Hyperarousal. [Rosenbaum 1998]. Risk factors of ADS can play a profound role in discontinuation of antidepressant. Risk factors such as doses higher than the minimum effective dose of SSRI/SNRI are required for a desired therapeutic effect, withdrawal symptoms were experienced after non-adherence, previous failed attempts at discontinuing antidepressant treatment. [Harvey,2014]. Studies have shown that patients on SSRI/SNRI for a period of less than 6 to 8 weeks are less at risk of developing ADS [Haddad,2007] Symptoms of ADS usually occur within a few days after stopping an antidepressant, or less often after reducing the dose. Withdrawal symptoms usually disappear completely within 24 hours when the original antidepressant, or a pharmacologically similar agent, is reinitiated [Haddad,2007]. If the symptoms disappear after a restart of the antidepressant, or returning to a previous higher dose, without residual complaints within a few days, discontinuation symptoms are most likely to occur.

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SSRI tapering schedule based on only half-life: Citalopram 20- Escitalopram Fluvoxamine Fluoxetine Paroxetine Sertraline 40mg 10-20mg 100-200mg 20-60mg 20-60mg 50-200mg (36hrs) (27-32hrs) (14-16hrs) (4-6 days) (24hrs) (26hrs)

Wk1 30mg 20mg 200mg 20mg 40mg 50mg

Wk2 20mg 10mg 100mg 0mg 30mg 25mg

Wk3 10mg 5mg 50mg 20mg 0mg

Wk4 0mg 0mg 0mg 10mg

Wk5 0mg ● For doses above the minimum effective, taper for at least 2-4 week at a rate of 25% [Ogle 2013]

SNRI tapering schedule based on half-life: Duloxetine Venlafaxine ER Desvenlafaxine 60-120mg 75-375mg 50-400mg (8-17hrs) (10-13hrs) (10-11hrs)

Wk1 60mg 75mg 50mg

Wk2 30mg 37.5mg 30mg

Wk3 0mg 0mg 0mg

Management of antidepressant discontinuation syndrome If ADS does occur, the patient must be made aware of ADS symptoms before initiation of a tapering schedule. The patient must be assured that these symptoms are non-life threatening and will subside in approximately 1-2 weeks duration. A common approach to resolving ADS is to restate the antidepressant at the initial dose and procedure with a slower tapering schedule. Another way to counteract ADS is to replace the minimum dose of an SSRI or SNRI with fluoxetine 20 mg/day for a duration of at least seven days. Fluoxetine can then be terminated due to his long half-life with no tapering required.[Giakas, 1997]

Gabapentin induced hypersensitivity syndrome: ● There have only been a few case reports with details describing gabapentin-induced hypersensitivity (Geata et al. 2008; Ragucci 2001). ● Typically, other such as , , and would incite a hypersensitive reaction (DRESS, SJS, TENS, etc.), and is generally mitigated using gabapentin as an when other options are exhausted. ● Gabapentin is currently indicated as add-on therapy for partial seizures which do not have adequate control with other anticonvulsants, and to reduce from diabetic and postherpetic neuropathy. ● Gabapentin has been used after a hypersensitivity reaction to other anticonvulsants successfully, mainly because the induction of a hypersensitive reaction is rare in the use of gabapentin (Hamer 1999).

Recommendations exist for nonaromatic antiepileptics e.g. , tiagabine, gabapentin, , and , have a low risk of serious immune-related reactions, and may be used in patients with a history of immune-mediated reactions to other antiepileptics (Gaeta 2008).

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Mitigating side effects of gabapentin withdrawal: ● About 40-65% of people who are on gabapentin misuse the drug (Smith 2016). ● Patients taking moderate to high doses of gabapentin (700 mg q day to 2400 mg TID) have been shown to exhibit withdrawal symptoms from as early as 12 hours to 7 days (Norton 2001; Finch 2010; Mersfelder 2016). Symptoms typically present as anxiety, diaphoresis, palpitations, , agitation, migraines, , tachycardia, hypertension, and insomnia. There is a worry that as the antiepileptic is decreased, the threshold is also decreased, resulting in possible seizures upon abrupt discontinuation of gabapentin. More serious side effects such as akathisia, catatonia, and seizures have occurred in patients experiencing withdrawal (Mersfelder 2016). ● The symptoms reported from various cases and case series from a span of 22 years were resolved upon the restart of the dose of gabapentin that the patient was previously on (Mersfelder 2016). The patient who had a seizure was controlled with and phenytoin. ● Some patients who presented with withdrawal symptoms were started on a +/- haloperidol with mixed results (most of the patient’s symptoms were not controlled), and typically had to be reinitiated back on the gabapentin to come back to baseline (Mersfelder 2016).

Gabapentin and the BEER’s Criteria: ● ( and gabapentin) which had been on the list to be used in only low doses due to ataxia and falls are now recommended to be avoided in combination with due to sedation, respiratory , and death (Ruscitella 2019). ● New recommendations include avoiding the use of opioids concurrently with and avoiding the use of opioids concurrently with gabapentinoids (except when transitioning from the former to the latter), due to the enhanced effects of the opioids (AGS 2019).

Gabapentin discontinuation strategy: ● Opting for a slower gabapentin taper (>5 days) maybe warranted, that a gabapentin taper should cautiously follow a regimen similar to a benzodiazepine taper, with a course that is done slowly and over a period of weeks to months. ● It has been shown in one case that a patient who had been taking gabapentin for 5 years (at 400 mg BID per day), had been tapered off gabapentin over a span of 5 days at a decrease of 100 mg BID per day, and started on a low dose of (150 mg q HS then BID over a few days after initiation), and exhibited symptoms that mimic or benzodiazepine withdrawal (Tran 2005). The patient returned to baseline upon the recontinuation of gabapentin. ● Tapering regimens should be individualized with consideration for factors such as lifestyle, personality, environmental stressors, reasons for taking gabapentin, and amount of available personal and clinical support. Cost to the patient with the continued visits should also be accounted for.

Proposed Gabapentin Tapering Regimen: Dose Reduction: Reduce the daily dose by 100-300 mg each week, while monitoring for withdrawal

Example

Wk1 600 mg TID → 600 mg BID and 400 mg q HS

Wk2 600 mg BID and 400 mg q HS → 600 mg q AM and 400 mg BID

Wk3 600 mg q AM and 400 mg BID → 400 mg TID

Wk4 400 mg TID → 400 mg BID and 100 mg q HS

Onward Continue a regimen that is cost efficient and does not impose too much of a pill burden until discontinuation. Always monitor for any new or unusual withdrawal effects (anxiety, diaphoresis, palpitations, confusion, agitation, migraines, tremor, tachycardia, hypertension, insomnia, akathisia, catatonia, and seizures).

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NOTE: This is merely one way of tapering a patient off of gabapentin and should not be used for all scenarios. Clinical judgment and taking into account the patient specific variables still need to be applied.

● Gabapentin is supplied in (per Micromedex): ○ Capsules: 100 mg, 300 mg, and 400 mg ○ Tablets: 600 mg and 800 mg ○ Solution: 250 mg/ 5mL ○ Gralise ER tablets: 300 mg and 600 mg

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