What alternative anxiety medication can be used if you cannot tolerate an SSRI?

Generalized anxiety disorder (GAD) is often treated with selective serotonin reuptake inhibitors (SSRIs) such as escitalopram, sertraline or paroxetine. Trials show that only 50% to 60% of people respond to these medications, remission rates are between 25% and 35%, and many people have significant side effects. Pharmacogenetic testing, which shows how your DNA affects the way you process medications, can help explain why some people cannot tolerate SSRIs and help predict how other anxiety medications will work for them. It reports whether you are a normal, intermediate, rapid, ultrarapid or poor metabolizer for commonly prescribed medications.

Some people with GAD have SSRI-related sexual side effects, worsening anxiety or sleep problems. There are several reasons for SSRI intolerance, explained in Wondering why you can't tolerate antidepressants?

Below is an overview of other medications used for anxiety, and how genetic differences affect how well they work and how well they are tolerated.

Should you stop your SSRI if you have side effects?

Not on your own. Stopping an SSRI suddenly can cause withdrawal symptoms and a return of anxiety. Talk to your doctor or pharmacist first. They can adjust the dose, switch you to another medication, or use your pharmacogenetic results to guide the choice.

Which medications do Canadian guidelines recommend for GAD?

The Canadian clinical practice guidelines for anxiety disorders group GAD medications by line of treatment:

• First-line: agomelatine*, duloxetine, escitalopram, paroxetine, pregabalin, sertraline and venlafaxine XR.
• Second-line: benzodiazepines (such as alprazolam, bromazepam, diazepam and lorazepam), bupropion XL, buspirone, hydroxyzine, imipramine, quetiapine XR and vortioxetine.
• Third-line: citalopram, divalproex, fluoxetine, mirtazapine and trazodone.

*Agomelatine is not available in Canada.

Duloxetine and venlafaxine

Duloxetine (Cymbalta) and venlafaxine XR (Effexor XR) belong to a family of medications called serotonin-norepinephrine reuptake inhibitors (SNRIs). Both are first-line treatments for GAD. Duloxetine may also help people with nerve pain or fibromyalgia.

Duloxetine is broken down in the liver by two enzymes, CYP1A2 and CYP2D6. According to the 2023 guideline from the Clinical Pharmacogenetics Implementation Consortium (CPIC), CYP2D6 poor or ultrarapid metabolizers may have more side effects or a weaker response to duloxetine, but there are no specific dose adjustment recommendations. Drug interactions also matter: duloxetine should not be combined with strong CYP1A2 blockers such as fluvoxamine. In a study reported in the duloxetine prescribing information, taking fluvoxamine with duloxetine raised duloxetine levels in the blood about six-fold.

Venlafaxine is broken down mainly by CYP2D6. For people who are CYP2D6 poor metabolizers, CPIC recommends considering another antidepressant that does not depend mainly on CYP2D6.

Desvenlafaxine (Pristiq) is the active form of venlafaxine. It is broken down by the CYP3A4 enzyme rather than CYP2D6, so CYP2D6 results do not affect it. In Canada it is approved for depression rather than GAD, but your doctor may consider it if you are a CYP2D6 poor metabolizer.

How do your genes affect SSRIs and SNRIs?

Two liver enzymes, CYP2D6 and CYP2C19, process most SSRIs and SNRIs. Sertraline also depends on a third enzyme, CYP2B6. Their activity varies widely between people and across ancestries. In simple terms, the 2023 CPIC guideline recommends:

Medication	Gene	What CPIC recommends
Escitalopram, citalopram	CYP2C19	Ultrarapid or poor metabolizers: consider another medication (or a lower dose for poor metabolizers). Rapid metabolizers: usual dose, adjusted if it does not work well.
Sertraline	CYP2C19, CYP2B6	CYP2C19 poor metabolizers: half the usual starting dose, or another medication. CYP2B6 poor metabolizers: a lower starting dose and a lower maintenance dose. CYP2B6 intermediate metabolizers: a slower dose increase and a lower maintenance dose. When both genes are affected, the dose may need adjusting even if neither result alone would require it.
Paroxetine	CYP2D6	Ultrarapid metabolizers: another medication. Poor metabolizers: half the usual dose.
Fluvoxamine	CYP2D6	Poor metabolizers: a lower starting dose, or another medication.
Vortioxetine	CYP2D6	Ultrarapid metabolizers: another medication. Poor metabolizers: half the usual starting dose and a lower maximum dose, or another medication.
Venlafaxine	CYP2D6	Poor metabolizers: consider another medication.

Your prescriber chooses the exact medication and dose with you.

General side effects of SNRIs

SNRIs may cause headaches, drowsiness or trouble sleeping, nervousness, nausea, dry mouth, weight loss and increased sweating. People starting an SNRI should be followed to check that it works and is well tolerated, and their other health conditions should be considered to make sure it is the right medication.

Buspirone

Buspirone (Buspar) is an anxiety medication that works differently from SSRIs and SNRIs. It is a second-line treatment for GAD. Buspirone is broken down by the CYP3A4 enzyme, so medications that block CYP3A4, and grapefruit juice, can raise its levels and its side effects. Your pharmacist can check for these interactions.

Hydroxyzine and bupropion

Hydroxyzine is an antihistamine that can ease anxiety and is a second-line option for GAD. It often causes drowsiness, so it needs caution in older adults. Bupropion XL is also listed as a second-line option for GAD, although the evidence for anxiety is more limited than for depression. Learn more in Bupropion (Wellbutrin) as an alternative medication for SSRI intolerance.

Anxiety medications not affected by pharmacogenetics

Pregabalin (Lyrica) is a first-line treatment for GAD in Canadian guidelines and is approved for GAD in Europe. In Canada it is approved for nerve pain and fibromyalgia, so its use for anxiety is off-label. It is more sedating than SSRIs, which can help people whose anxiety disrupts their sleep, and it may work faster. It can cause dizziness and drowsiness, increases the risk of falls in older adults, and has some potential for misuse. Gabapentin is a related medication sometimes used off-label for anxiety, with less evidence.

Pregabalin and gabapentin are cleared by the kidneys, not by liver enzymes, so pharmacogenetic results do not change their dosing. Kidney function does.

Other less common options

Benzodiazepines such as alprazolam are second-line options, but they are generally used only for short periods. They can cause drowsiness, memory problems, falls and car accidents, and they carry a risk of dependence.

For severe anxiety that does not respond to other treatments, some antipsychotics may be added. Quetiapine XR has the most evidence in GAD.

Summary

• Several medications other than SSRIs are recommended for GAD, including SNRIs, pregabalin, buspirone, hydroxyzine and bupropion XL.
• Pharmacogenetic results can show which SSRIs and SNRIs, and which doses, are more likely to suit you.
• Pharmacogenetic testing can help reduce the number of medication trials, improve tolerability and support staying on treatment.
• Clinical pharmacists can help physicians optimize medications, especially for people with complex drug metabolism who cannot tolerate SSRIs.

Frequently asked questions

What can I take for anxiety if I can't tolerate an SSRI?

Canadian guidelines list several options for generalized anxiety disorder, including the SNRIs duloxetine and venlafaxine XR, pregabalin, and second-line options such as buspirone, hydroxyzine and bupropion XL. Your doctor will choose based on your symptoms, other conditions and medications.

Should I stop my SSRI if it causes side effects?

Not on your own. Stopping suddenly can cause withdrawal symptoms and a return of anxiety. Talk to your doctor or pharmacist first.

Can a pharmacogenetic test help choose an anxiety medication?

Yes, for medications processed by CYP2D6, CYP2C19 or CYP2B6. The 2023 CPIC guideline gives gene-based advice for escitalopram, citalopram, sertraline, paroxetine, fluvoxamine, vortioxetine and venlafaxine.

Which anxiety medications are not affected by my genes?

Pregabalin and gabapentin are cleared by the kidneys, so pharmacogenetic results do not change their dosing.

References

Katzman MA, Bleau P, Blier P, et al. Canadian clinical practice guidelines for the management of anxiety, posttraumatic stress and obsessive-compulsive disorders. BMC Psychiatry. 2014;14 Suppl 1:S1.

Bousman CA, Stevenson JM, Ramsey LB, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6, CYP2C19, CYP2B6, SLC6A4, and HTR2A Genotypes and Serotonin Reuptake Inhibitor Antidepressants. Clin Pharmacol Ther. 2023;114(1):51-68.

Roy-Byrne P. Treatment-refractory anxiety; definition, risk factors, and treatment challenges. Dialogues Clin Neurosci. 2015;17(2):191-206.

Jakubovski E, Johnson JA, Nasir M, Müller-Vahl K, Bloch MH. Systematic review and meta-analysis: Dose-response curve of SSRIs and SNRIs in anxiety disorders. Depress Anxiety. 2019;36(3):198-212.

Zhou Y, Ingelman-Sundberg M, Lauschke VM. Worldwide Distribution of Cytochrome P450 Alleles: A Meta-analysis of Population-scale Sequencing Projects. Clin Pharmacol Ther. 2017;102(4):688-700.

CYMBALTA (duloxetine) prescribing information. DailyMed, US National Library of Medicine.