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

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

Reviewed by Alison Wong, RPH.

Generalized anxiety disorder (GAD) is generally treated with Selective Serotonin Reuptake Inhibitors (SSRIs). First line SSRIs for GAD treatment include citalopram, escitalopram and sertraline. Clinical trials show response rates of 50% to 60%, remission rates between 25% and 35% and a significant proportion of patients who experience significant SSRI side effects and want to try other medications. Other possible treatment options for GAD include serotonin-norepinephrine reuptake inhibitors (SNRIs), buspirone, hydroxyzine, pregabalin, and bupropion. A prescribing algorithm for GAD treatment is available at psychopharm.mobi.

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 impact on tolerability and response.

Duloxetine (Cymbalta) and venlafaxine (Effexor) are 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 preferred because it may have less sexual side effects than venlafaxine. Duloxetine is cleared by CYP2D6 and CYP1A2. Concomitant administration of duloxetine with fluvoxamine, a potent CYP1A2 inhibitor, to Poor Metabolizers resulted in a six-fold increase in duloxetine blood levels (AUC and Cmax) when compared with Normal Metabolizers, leading to significant side effects. Venlafaxine is also metabolized by CYP2D6. For CYP2D6 poor (PM) and intermediate metabolizers (IM), the Royal Dutch Pharmacists Association – Pharmacogenetics Working Group (DPWG) guidelines recommend an alternative to venlafaxine or to adjust the dose to clinical response and to monitor the patient’s plasma metabolite level. For CYP2D6 ultrarapid metabolizers(UM), the DPWG guidelines suggest to titrate the dose to a maximum of 150% of the normal dose or to select an alternative to venlafaxine.

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. Poor and Ultrarapid metabolizers should not be prescribed these medications due to the availability of other alternatives. Other SNRIs, such as desvenlafaxine and levomilnacipran, are metabolized by the CYP3A4 enzyme, not the CYP2D6 and could be as alternative options.

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.

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 then buspirone is co-prescribed with CYP3A4 substrate or inhibitors.

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 anxiolytic. Gabapentin and pregabalin are mostly eliminated renally (not through the liver) and are therefore unlikely to be influenced by pharmacogenetic variations.

Although the FDA has approved alprazolam for GAD, benzodiazepines are generally not recommended as alternatives to SSRIs for treatment of anxiety because of its sedative effects which can lead to automobile accidents, increased risk of falls and impaired memory. Benzodiazepines are also associated with abuse potential.

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 could be used for treatment of anxiety. Pharmacogenetic testing can help to reduce the number of SSRI trials, improve tolerability and adherence to treatment. Clinical pharmacists can assist physicians to optimize medication management, particularly for patients with complex drug metabolic profiles who frequently present as “treatment resistant” or intolerant to SSRIs.


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

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.

Share this post