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Antidepressants not working: four alternative medications your doctor should consider

The treatment and diagnosis of mental health conditions is posing challenges for family physicians. Patients with symptoms of anxiety and depression frequently do not respond to antidepressants leading to multiple trials with different drugs. Only when a patient has failed several drug trials s/he is referred to psychiatrist for re-evaluation. In many provinces, access to psychiatrists quite is limited and frequently requires  a long wait time.

There are multiple reasons why antidepressants do not work for patients, and the two most common are:

  • Incorrect drug or antidepressant dose
  • Incorrect diagnosis

Pharmacogenetic tests like Pillcheck can help patients get on the right medication and dose faster, leading to more effective treatment.  In short, a patient can feel better, sooner with the peace of mind he or she is on the right medication.

Following is an in-depth discussion of the reasons that some patients don’t respond to certain antidepressants or need a dosage adjustment.  If you or someone you know has been diagnosed with depression and medications aren’t working, share this information with a doctor.

Selective Serotonin Reuptake Inhibitors (SSRIs) are the first line of treatment for depression and anxiety. Most SSRIs are metabolized by the liver enzymes called CYP2C19 and CYP2D6. People who have inherently reduced or enhanced activity of these enzymes may not respond to antidepressants or may experience significant side effects.  Pharmacogenetic testing can help you and your doctor to assess what type of metabolizer you are, and guide SSRI selection and dose. Psychiatric experts, Dr. Chiara Fabbri and Dr Alessandro Serretti, comment that pharmacogenetic testing has some advantages when compared with regular therapeutic drug monitoring on its own:

PGx testing can save time that would be spent waiting for the drug to reach steady-state concentration, and the results of the test remain the same life-long so there is no need for retesting.”

However, SSRI intolerance might be not related to drug metabolism: some mental health conditions disrupt serotonin balance and SSRIs may cause further worsening of symptoms.  Patients with bipolar disorder typically do not respond well to SSRIs, and are better managed with antipsychotics including quetiapine, lurasidone, lithium, lamotrigine, and their combinations. In fact, the CANMAT/ISBD Treatment Guidelines for 2018 recommend against the use of antidepressants in bipolar type I.

Bipolar disorder is characterized by extreme shifts in mood when periods of depression occur along with periods of extremely elevated mood, called mania. For some with bipolar disorder, episodes of mood swings are quite irregular and can occur several times a year, while others may experience manic episodes very rarely.  Because of this, experts acknowledge the difficulty distinguishing bipolar depression from unipolar depression: DSM-IV-TR clearly specifies that bipolar affective disorder cannot be diagnosed until an individual has suffered at least one episode of mania, which can result in selection of the wrong approach to treatment.

Patients presenting with severe mood swings, i.e. manic episodes, are classified as bipolar I, while patients with milder symptoms classified as bipolar 2. In bipolar 2 severe depression periods transition to hypomanic episodes. In bipolar 2, antidepressants are second-line options but only for “pure depression”.

If your pharmacogenetic report shows that you have normal CYP2D6 and CYP2C19 function, i.e. your body should clear SSRIs at expected rate, but you still cannot tolerate these drugs, perhaps your doctor should refer you to a psychiatrist for diagnosis re-evaluation. Diagnostic features of bipolar depression include:

  • earlier depression onset that’s before age 25,
  • depression with psychotic features,
  • family history of bipolar disorder,
  • antidepressant-induced irritability or manic symptoms or rapid cycling,
  • atypical features such as excessive sleepiness (hypersomnia), abnormally increased appetite (hyperphagia), and heavy feelings in arms or legs (leaden paralysis).

If your mental health condition includes the features described above, your physician may recommend antipsychotic medications such as Lithium, quetiapine, divalproex, asenapine, aripiprazole, paliperidone, risperidone, and cariprazine.

CANMAT/ISBD Treatment Guidelines for bipolar I recommend quetiapine, lithium, divalproex, and lamotrigine, as well as lurasidone in a combination treatment with lithium or divalproex.

It is also important to recognize that antidepressant alone are specifically not recommended due to “negative evidence” i.e. studies have shown that SSRIs ae not effective in controlling depression symptoms. Lithium, quetiapine, divalproex, asenapine, aripiprazole, paliperidone, risperidone, and cariprazine alone or in combination are recommended as first-line treatments for acute mania.


  • Pharmacogenetic testing can identify whether antidepressant intolerance is caused by altered drug metabolism.
  • If a pharmocgenetic test of high sensitivity finds a patient has a normal pharmacogenetic profile for current drug therapy, this may warrant a diagnosis re-evaluation.
  • Patients who display the diagnostic features for a bipolar depression diagnosis should be treated with antipsychotic medications rather than with antidepressants.
  • Pharmacogenetic testing can also help to assess how antipsychotic medications are metabolized by your body.

Selected References:

Roy-Byrne, P., MD. Treatment-refractory anxiety; definition, risk factors, and treatment challenges. Dialogues Clin Neurosci. 2015 Jun; 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 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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