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

Generalized anxiety disorder (GAD) is   treated with Selective Serotonin Reuptake Inhibitors (SSRIs). Normally, people are first prescribed the SSRIs citalopram, escitalopram and sertraline. Trials show that only 50% to 60% of people respond to these medications, remission rates between 25% and 35% are achieved, and a large proportion of patients experience significant SSRI side effects. Pharmacogenetic testing, which determines how you respond to medications based on your unique DNA, can help individuals and their healthcare providers to understand why some cannot tolerate SSRIs and help predict how other anxiety medications will work for them.  Pharmacogenetic testing will indicate if an individual is a normal, intermediate, ultrarapid, or poor metabolizer for commonly prescribed medications.  It can help determine which of the other possible treatment options for GAD are right for an individual.  These include serotonin-norepinephrine reuptake inhibitors (SNRIs), buspirone, hydroxyzine, pregabalin, and bupropion. A prescribing algorithm, or process to be followed for GAD treatment is available at:

Some patients with GAD frequently experience SSRI-induced sexual side effects, worsening of anxiety or sleep disruption. There are multiple reasons for SSRI intolerance – you can find more details here.

Below we provide an overview of some alternative medications that can be used for treatment of anxiety and the role of pharmacogenetic variations that have an impact on tolerability and response.

Duloxetine and Venlafaxine

Duloxetine (Cymbalta) and venlafaxine (Effexor) come from another family of medications called SNRIs that are FDA-approved for the treatment of GAD. Duloxetine may also be useful for patients suffering from neuropathic pain and fibromyalgia. Duloxetine is ususally preferred because it may have less sexual side effects than venlafaxine does. Duloxetine is cleared in the liver by two important enzymes in drug metabolism called CYP2D6 and CYP1A2. Sometimes, duloxetine and the drug fluvoxamine are prescribed together.  Fluvoxamine is used to treat obsessive-compulsive disorder which often occurs with GAD.  People who do not metabolize duloxetine normally based on their pharmacogenetic profile may experience serious side effects because fluvoxamine interferes with CYP1A2 enzymes and is also metabolized by CYP2D6. In one study, poor CYP2D6 metabolizers of duloxetine experienced a six-fold increase of the the drug in their blood versus those who metabolize it normally. Excessive drug dose is one of the most common reasons why some people cannot tolerate SSRIs.

Venlafaxine is also metabolized by CYP2D6. For CYP2D6 poor and intermediate metabolizers,  the Royal Dutch Pharmacists Association – Pharmacogenetics Working Group (DPWG) guidelines recommend an alternative to venlafaxine or to adjust the dose to  and to monitor the patient’s plasma metabolite level. For CYP2D6 ultrarapid metabolizers, the DPWG guidelines suggest prescribing a dose to a maximum of 150% of the normal dose or to select an alternative to venlafaxine.

Ethnic Background and SNRIs

Depending on ethnic background, 30-50% of people in North America have inherently altered CYP2D6 activity and may experience side effects when treated with duloxetine or venlafaxine, and also cannot tolerate SSRIs such as fluoxetine and paroxetine. Poor and Ultrarapid metabolizers should not be prescribed these medications due to the availability of other, better alternatives. Other SNRIs, such as desvenlafaxine and levomilnacipran, are metabolized by the CYP3A4 enzyme, not the CYP2D6 and could be prescribed instead if a person’s pharmacogenetic profile indicates they are good alternatives.

General Side Effects

SNRIs may cause headaches, drowsiness or insomnia, nervousness, nausea, dry mouth, weight loss and increased sweating. Patients starting an SNRI should be monitored for efficacy of treatment as well as tolerability. When starting an SNRI, the patient’s other health problems should also be assessed by the healthcare provider to ensure that it is the correct medication.

The SNRI Buspirone (Buspar) is used for treatment of GAD and depression. Buspirone is metabolized by the CYP3A4 enzyme, which is involved in the metabolism of multiple medications. The activity of CYP3A4 can vary by a factor of 10-100 between individuals. About 15% of people in North America have inherently reduced CYP3A4 function; people carrying inactive alleles are at increased risk of drug-induced toxicity, especially when buspirone is co-prescribed with CYP3A4 substrate or inhibitors.

Generalized Anxiety Drugs not affected by Pharmacogenetics

Pregabalin (Lyrica) is an antiepileptic medication that commonly prescribed for anxiety in Europe and South America where it is approved for GAD, but in Canada and US it is approved for treatment of neuropathic pain in patients with diabetic peripheral neuropathy and postherpetic neuralgia. Pregabalin is more sedating than SSRIs and might be beneficial for anxiety patients experiencing insomnia. Furthermore, it has a faster response profile than SSRIs. Pregabalin should be used with caution in the elderly however because of increased risk of falls and somnolence. Gabapentin is another antiepileptic medication prescribed for neuropathic pain and seizures, but also frequently used off-label as an anti-anxiety treatment. Gabapentin and pregabalin are mostly eliminated through the kidneys or renally and not through the liver like SNRIs and SSRIs and are therefore unlikely to be influenced by a person’s pharmacogenetic profile.

Other less-common alternatives

Although the FDA has approved the tranquilizer alprazolam for generalized anxiety disorder, benzodiazepines, the class of drugs that alprazolam belongs to, are generally not recommended as alternatives to SSRIs for treatment of anxiety.  This is because of their sedative effects, which can lead to automobile accidents, increased risk of falls and impaired memory. Benzodiazepines are also associated with the potential for abuse.

In patients with severe uncontrolled anxiety, antipsychotic augmentation might also be considered. Medications that have been evaluated in this context include risperidone, olanzapine and quetiapine.


  • Pharmacogenetic test results can provide insight to which of the SSRIs and SNRIs should be used for the treatment of anxiety.
  • Pharmacogenetic testing can help to reduce the number of SSRI trials an individual requires, improve tolerability, and the adherence to treatment.
  • Clinical pharmacists can assist physicians to optimize medication management, particularly for patients with complex drug metabolic profiles who are frequently “treatment resistant” or cannot tolerate SSRIs.

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Canadian clinical practice guidelines for the management of anxiety, posttraumatic stress and obsessive-compulsive disorders. Katzman MA, Bleau P, Blier P, Chokka P, Kjernisted K, Van Ameringen M; Canadian Anxiety Guidelines Initiative Group on behalf of the Anxiety Disorders Association of Canada/Association Canadienne des troubles anxieux and McGill University, Antony MM, Bouchard S, Brunet A, Flament M, Grigoriadis S, Mendlowitz S, O’Connor K, Rabheru K, Richter PM, Robichaud M, Walker JR. BMC Psychiatry. 2014;14 Suppl 1:S1. doi: 10.1186/1471-244X-14-S1-S1. Epub 2014 Jul 2. Review.

Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 Clinical Guidelines for the Management of Adults with Major Depressive Disorder: Section 6. Special Populations: Youth, Women, and the Elderly. MacQueen GM, Frey BN, Ismail Z, Jaworska N, Steiner M, Lieshout RJ, Kennedy SH, Lam RW, Milev RV, Parikh SV, Ravindran AV; CANMAT Depression Work Group. Can J Psychiatry. 2016 Sep;61(9):588-603. doi: 10.1177/0706743716659276. Epub 2016 Aug 2. Review. Erratum in: Can J Psychiatry. 2017 May;62(5):356.

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 Mar;36(3):198-212.

Hicks JK et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 and CYP2C19 Genotypes and Dosing of Selective Serotonin Reuptake Inhibitors. Clin Pharmacol Ther. 2015 Aug; 98(2): 127–134.

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